Drug–Drug Interaction Primer
A Compendium of Case Vignettes for the Practicing Clinician

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Drug–Drug Interaction Primer
A Compendium of Case Vignettes for the Practicing Clinician
Neil B. Sandson, M.D.
Director, Division of Education and Residency Training, Sheppard Pratt Health System, Towson, Maryland; Associate Director, University of Maryland/Sheppard Pratt Psychiatry Residency Program; Clinical Assistant Professor, Department of Psychiatry, University of Maryland Medical System, Baltimore, Maryland

Contributors Scott C. Armstrong, M.D.
Medical Co-Director, Tuality Center for Geriatric Psychiatry, Forest Grove, Oregon; Associate Clinical Professor of Psychiatry, Oregon Health and Science University, Portland, Oregon

Kelly L. Cozza, M.D.
Psychiatrist, Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, D.C.; Assistant Professor, Department of Psychiatry, Uniformed Services University of the Health Sciences; Fellow, Academy of Psychosomatic Medicine, Bethesda, Maryland

Jessica R. Oesterheld, M.D.
Medical Director, Spurwink School, Portland, Maine; Instructor in Family Medicine, University of New England College of Osteopathic Medicine, Biddeford, Maine

Washington, DC London, England

Note: The authors have worked to ensure that all information in this book is accurate at the time of publication and consistent with general psychiatric and medical standards, and that information concerning drug dosages, schedules, and routes of administration is accurate at the time of publication and consistent with standards set by the U.S. Food and Drug Administration and the general medical community. As medical research and practice continue to advance, however, therapeutic standards may change. Moreover, specific situations may require a specific therapeutic response not included in this book. For these reasons and because human and mechanical errors sometimes occur, we recommend that readers follow the advice of physicians directly involved in their care or the care of a member of their family. Books published by American Psychiatric Publishing, Inc., represent the views and opinions of the individual authors and do not necessarily represent the policies and opinions of APPI or the American Psychiatric Association. To buy 25–99 copies any APPI title, you are eligible for a 20% discount; please contact APPI Customer Service at appi@psych.org or 800-368-5777. To buy 100 or more copies of the same title, please e-mail bulksales@psych.org for a price quote. Copyright © 2007 American Psychiatric Publishing, Inc. ALL RIGHTS RESERVED Manufactured in the United States of America on acid-free paper 11 10 09 08 07 5 4 3 2 1 First Edition Typeset in Adobe’s Janson and Myriad. American Psychiatric Publishing, Inc. 1000 Wilson Boulevard Arlington, VA 22209-3901 www.appi.org Library of Congress Cataloging-in-Publication Data Sandson, Neil B., 1965– Drug–drug interaction primer : a compendium of case vignettes for the practicing clinician / by Neil B. Sandson ; contributors, Scott C. Armstrong, Kelly L. Cozza, Jessica R. Oesterheld. — 1st. ed. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-58562-305-1 (pbk. : alk. paper) 1. Drug interactions—Case studies. I. Armstrong, Scott C. II. Cozza, Kelly L. III. Oesterheld, Jessica R. IV. Title. [DNLM: 1. Drug Interactions—Case Reports. QV 38 S221dd 2007] RM302.S32 2007 615′.7045—dc22 2007001493 British Library Cataloguing in Publication Data A CIP record is available from the British Library.

CONTENTS
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

1 Core Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 Psychiatry Case Vignettes . . . . . . . . . . . . . . . . . . . . . . . . 13 3 Internal Medicine Case Vignettes . . . . . . . . . . . . . . . . 107 4 Neurology Case Vignettes . . . . . . . . . . . . . . . . . . . . . . . 187 5 Surgery/Anesthesia Case Vignettes . . . . . . . . . . . . . . 217 6 Gynecology, Oncology, and
Dermatology Case Vignettes . . . . . . . . . . . . . . . . . . . 229 Appendix A: An Overview of Psychotropic Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . 243
Neil B. Sandson, M.D. Scott C. Armstrong, M.D. Kelly L. Cozza, M.D.

Appendix B: P450 Tables . . . . . . . . . . . . . . . . . . . . . . . . 343
Kelly L. Cozza, M.D. Scott C. Armstrong, M.D. Jessica R. Oesterheld, M.D.

Appendix C: UGT or Phase II (Glucuronidation) Tables . . . . . . . . . . . . . . . . . . . . . . .361
Jessica R. Oesterheld, M.D.

Appendix D: P-Glycoprotein Table . . . . . . . . . . . . . . . 367
Jessica R. Oesterheld, M.D.

Case Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377

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ACKNOWLEDGMENTS

This book is again dedicated to my two wonderful children, Charlie and Lisa. Once again, abundant and heartfelt thanks to my helpful wife (who is becoming a drug–drug interaction maven in her own right) and all my friends, family, and coworkers who provided moral and material support. This was a team effort, and you made it possible. Special thanks again to Dr. Steven Sharfstein for his patronage and guidance. I also want to thank Dr. Tom Wise, for granting permission to reprint my review article from Psychosomatics for this edition of the book. Thanks again to Drs. Cozza, Armstrong, and Oesterheld for their warm welcome into the “P450 family” and ongoing mentorship. And again, thanks to my parents for getting me pointed in the right directions. I would also like to thank the following people who contributed clinical vignettes: • • • • • • • • • • • • • • • • Scott C. Armstrong, M.D. Daniela Boerescu, M.D. Kelly L. Cozza, M.D. Gabriel Eckermann, M.D. Sunil Khushalani, M.D. Christian Lachner, M.D. Michael Levinson, M.D. Lily Lin, Pharm.D. Raymond Love, Pharm.D. Catherine Marcucci, M.D. Jessica R. Oesterheld, M.D. Steven Ruths, M.D. Joseph Sokal, M.D. Susan Strahan, M.D. Ken Walters, Pharm.D. Edward Zuzarte, M.D.

vii

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a chance to revise and improve on one’s original work. there have been many changes. ethinylestradiol. didactic material cannot. All of the old caveats still apply. A challenge has been to make this version better than the first. Now the chapters represent clinical orientations.g. which is a reprint of a review article that I authored for Scott Armstrong’s and Kelly Cozza’s “Med-Psych Drug–Drug Interactions” column in the journal Psychosomatics in 2005.INTRODUCTION Second editions present a rare opportunity in life. antipsychotics.. This is not to say that readers should limit themselves only to the chapters that represent their specific interests. The cases were previously arranged by mechanism of interaction. I continue to hope that a case series format will help to bring the material alive in a way that dryer. due either to redundancy or to flaws that became apparent only recently. The cases have also been organized in an entirely different manner. There are 29 new cases and 31 of the old cases have been deleted. Every patient is different. Of special interest is Appendix A. Toward that end. and cases that might be of particular interest to a subspecialty within the field of medicine have been grouped accordingly. Some DDIs that will prove troublesome or even dire for one patient may be well tolerated or even beneficial for anix . I’ve enjoyed this chance to expand on some themes that were only briefly explored in the Drug Interactions Casebook: The Cytochrome P450 System and Beyond. Some of the assignments to particular chapters have been close calls in which a case could reasonably be placed in any of two or three different chapters. This review contains the metabolic pathways and inhibitory and inductive profiles for antidepressants. and mood stabilizing agents as well as tables that detail all known and clinically significant drug–drug interactions (DDIs) between pairings of any two agents from these drug classes. statins). tobacco. There is also a table detailing DDIs involving a few psychotropics not included in these three broad classes as well as select nonpsychotropic agents (e. It has also been nice to fix a few unfortunate errors that crept into the original. There is something in these cases for everyone.

In addition to the aforementioned psychotropic DDIs appendix. M. and phenytoin. Of course. and P-glycoprotein substrates. 2nd Edition (Cozza et al. theoretical case has been introduced. you will discover those cases in short order. phase II. Every case derives from sound clinical evidence. May all your interactions be benign. Armstrong SC. REFERENCE Cozza KL. interesting.x Drug–Drug Interaction Primer other.D. It will very quickly bring you up to speed on how to think about DDIs and begin to grapple with this daunting mountain of material. 2nd Edition. Sandson has no competing interests or conflicts to report. If you use the index to find cases involving valproate. this will be explicitly mentioned in the discussion section. inhibitors. Again. Sandson. this edition also explores the paradigm of plasma protein binding–mediated DDIs in some detail. P-Glycoproteins. this book is well indexed for concise searches to learn about particular DDIs. I again welcome you to take a journey into this complex. UGTs. No case represents a mere extrapolation from in vitro information about drug characteristics. DC. Neil B. and inducers. With that. you will also find tables detailing P450. P-Glycoproteins. 2003) remains the single best resource and reference for this material. Oesterheld J: Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s. 2003 Dr. However. . Washington. For readers new to this topic. in my opinion. and important world of DDIs. I do recommend starting with the “Core Concepts” section. UGTs. aspirin. In the rare instance in which a more conjectural. American Psychiatric Publishing. this book does not represent an exhaustive approach to this topic. For those who are interested. The Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s. the updated version of this book should bring more original material that will not be found there or elsewhere.

genus. Second Edition (Cozza et al. These enzymes perform phase I. or oxidative. but the several that are examined in this book account for more than 90% of P450 metabolism (Guengerich 1997). P450 SYSTEM The P450 system is a set of enzymes (usually hepatic. 2003). I provide concise explanations of the concepts and terms that are used throughout the various cases in subsequent chapters. P-Glycoproteins.Chapter 1 CORE CONCEPTS In this chapter. which provides such a review. 1 . These explanations are designed to enable the P450 neophyte to dive right in and begin reading the cases. The interested reader should consult Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s. UGTs. There are more than 40 P450 enzymes. but not always) that catalyze the metabolism of a wide array of endogenous and exogenous substances in order to detoxify them and then eliminate them from the body. This sequence is the rough equivalent of “family. Each P450 enzyme is named by a number-letternumber sequence (such as “1A2” or “3A4”). 2C9 and 2C19 are more closely related and share more common substrates than do 2C9 and 3A4. metabolism as opposed to phase II conjugation. This chapter is not intended to provide a comprehensive review of these topics. species” as a way of identifying members of the animal kingdom and serves to identify specific P450 enzymes.

the allosteric inhibitor renders the enzyme less efficient in metabolizing all substrates of that enzyme.2 Drug–Drug Interaction Primer SUBSTRATE The substrate is the agent whose metabolism is catalyzed by an enzyme into a metabolic end product. is when two substrates compete for the same substrate binding site(s) on an enzyme. This is a purely quantitative concept. with some trends within specific ethnic groups. In so doing. noncompetitive inhibition. there is just more of it. Enzymatic inhibition comes in two main varieties. The introduction of inhibitors leads to substrate accumulation and decreased metabolite formation. 1995). or inhibits. Inhibitors of P450 enzymes generally act within hours to days as a function of their half-lives. Usually this results in eventual deactivation of the agent in preparation for elimination from the body. The produced enzyme is no more intrinsically active than otherwise. the functioning of the enzyme or enzymes that metabolize substrates. occurs when an agent binds to a non-substrate binding site on an enzyme. these agents are initially inactive and rely on enzymes to be metabolized into active compounds. for example) across the world population (Ketter et al. VARIABILITY There is vast interindividual variability in enzymatic efficiency (10. leading to increased metabolism of the substrates of the induced enzyme. Induction of P450 enzymes can be evident within several days but generally takes 2–3 weeks to reach full effect. The competitive inhibitor binds so avidly to this substrate binding site that it effectively displaces the other substrate(s). competitive inhibition.to 30fold differences in 3A4 function. This does not even consider those individuals who lack copies of the genes that . The introduction of inducers leads to increased metabolite formation and more rapid depletion of substrate(s). The first. INHIBITOR An inhibitor interferes with. but the enzyme otherwise functions normally. which determine when they are able to gain access to and then inhibit the enzymes in question. The second type of inhibition. In the less frequent case of pro-drugs. INDUCER An inducer is an agent that causes the liver (or other target organ) to produce more of an enzyme.

P-glycoprotein inducers increase the amount of active P-glycoprotein and thus lead to more extrusion of P-glycoprotein substrates. URIDINE 5′-DIPHOSPHATE GLUCURONOSYLTRANSFERASES Uridine 5′-diphosphate glucuronosyltransferases (UGTs) are a family of enzymes that perform phase II conjugative metabolism (glucuronidation). P-glycoprotein is designed to remove substances from enterocytes and send them back into the gut lumen or from the cytosol of central nervous system capillaries back into the blood. individuals who have extra copies of P450 genes are referred to as ultrarapid metabolizers. Conversely. who are referred to as poor metabolizers for the specific P450 enzymes in question. It plays a central role in determining to what degree various substances are absorbed into or excreted from the body.g. By contrast. . with each enzyme having its own substrates. and inducers. In general. metabolically normal individuals (called extensive metabolizers) who are exposed to an agent that strongly inhibits a given P450 enzyme are functionally converted to poor metabolizers with regard to that specific P450 enzyme for as long as they are exposed to that agent. individuals exposed to an inducer may function as ultrarapid metabolizers for that P450 enzyme. Poor metabolizers will generally have much higher blood levels of a substrate at a given dosage than will extensive metabolizers. P-glycoprotein substrates are extruded and P-glycoprotein inhibitors antagonize this process and lead to greater absorption and distribution of P-glycoprotein substrates. inhibitors. P-GLYCOPROTEIN P-glycoprotein is one of a superfamily of transporters that line the gut and the blood-brain barrier. 2B15). inhibitors. and inducers.. the rate at which poor metabolizers metabolize a substrate of that enzyme is not influenced by introducing an inhibitor of that enzyme. which usually follows the phase I oxidative metabolism performed by P450 enzymes or other oxidative metabolic steps. An extruding transporter. This system is structured quite similarly to the P450 system in that several of its enzymes also have alphanumeric labels (e. Although this is counterintuitive. There is no way to become an ultrapoor metabolizer. 1A4.Core Concepts 3 code for various P450 enzymes. The inhibitor is redundant. P-glycoprotein has substrates.

Although there are no actual poor metabolizers. many antipsychotics. then 3A4 often serves as the backup enzyme. 2D6 is the usual starting point for any journey into the world of P450. and inducers. Vandamme et al. 1993). most 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors. macrolides. Quinidine is an extremely potent 2D6 inhibitor (von Moltke et al. 2002). and steroid compounds. and various antiarrhythmic agents (Funck-Bretano et al. 1993. 3A4 The enzyme 3A4 is the workhorse of the P450 system. 1986). 1995. and ritonavir (Cozza et al. von Bahr et al. 2003). protease inhibitors.4 Drug–Drug Interaction Primer BRIEF REVIEW OF SPECIFIC P450 ENZYMES 2D6 Although not the most important of the P450 enzymes. rifampin. It constitutes roughly 25%–30% of the liver’s P450 complement. 1991). Common substrates include tertiary-amine TCAs. 1989. macrolides. 1995). carbamazepine. 1989. protease inhibitors. There are no verified inducers of 2D6 (Madan et al. β-blockers (Lennard et al. Several of the selective serotonin reuptake inhibitors (SSRIs) are significant inhibitors of 2D6 (Lam et al. calcium-channel blockers. When other enzymes that would ordinarily serve as the primary catalysts for the metabolism of various drugs are unavailable. Shin et al. 1994). triazolobenzodiazepines. John’s wort. inhibitors. 2002). Fourteen percent of Caucasian individuals are poor metabolizers for 2D6. . Common inducers include several anticonvulsants. phenothiazines (Dahl-Puustinen et al. and there is also a significant 3A4 presence in the gut (DeVane and Nemeroff 2002). there is vast (10.to 30-fold) variability in the efficiency of 3A4 functioning across the human population (Ketter et al. 2003). The genetics of 3A4 are complex. and some of the antifungals. There is a vast array of 3A4 substrates. and quinolones. whereas 1%–3% of all individuals are ultrarapid metabolizers (Eichelbaum and Evert 1996). Sawada and Ohtani 2001). yet it is involved in a number of clinically significant drug interactions. as are TCAs (Lamard et al. Dahl et al. The 2D6 enzyme constitutes only 1%–2% of the P450 complement of the liver. Typical substrates include tricyclic antidepressants (TCAs. because this was the first P450 enzyme with which psychiatrists became familiar. either by virtue of potent exogenous inhibition or polymorphisms that code for a poor metabolizer phenotype. Common inhibitors include some of the SSRIs and nefazodone. St.

• Fluoxetine and fluvoxamine are inhibitors of 2C9 and 2C19 (Christensen et al. Harvey and Preskorn 2001. and 1A2. Mamiya et al. 1998). carbamazepine (Parker et al. 2001. and 2E1 The remaining major P450 enzymes. 1998) of 2C9 and 2C19. Rasmussen et al. account for substantially fewer psychotropic drug interactions than do 2D6. If the substrate has a low therapeutic index. • S-Warfarin is a 2C9 substrate (Heimark et al. Major issues include the following: • Phenytoin is both a substrate (Cadle et al. There are polymorphisms for 2C9 and 2C19. 1987. Alam and Sharma (2001) identified three distinct 1A2 alleles besides the wild type. Common 1A2 inhibitors include quinolones (Batty et al. 1998). Linder and Valdes 1999). . Zevin and Benowitz 1999). 2C19. 1995). 2002. 1995). Zhang and Kaminsky 1995). but they are only infrequently clinically relevant for psychiatrists (Alam and Sharma 2001). Greenblatt et al. 2C19. 1996). 2B6. and 2E1. fluvoxamine (Brosen 1995). 1994.Core Concepts 5 1A2 The 1A2 enzyme constitutes 13% of the liver’s P450 complement and is found only in the liver (DeVane and Nemeroff 2002). and grapefruit juice (Fuhr 1998). 1999. 3A4. 2B6. Polymorphisms for 1A2 do exist. olanzapine (Callaghan et al. PATTERNS OF P450 DRUG–DRUG INTERACTIONS There are six basic patterns of P450 drug–drug interactions. Niemi et al. Kall et al. 1998). some antiarrhythmic agents (Kobayashi et al. Common 1A2 substrates include TCAs (Sawada and Ohtani 2001. 1998. 2C9. Common 1A2 inducers include tobacco smoking (Schrenk et al. 1999). Nakajima et al. Pattern 1: An Inhibitor Is Added to a Substrate Adding an inhibitor to a substrate generally results in increases in substrate levels. clozapine (Eiermann et al. 1998. charred meats and several cruciferous vegetables (Jefferson 1998. 1997). and rifampin (Wietholtz et al. 1998) and an inducer (Chetty et al. Jefferson and Greist 1996. and xanthines (Miners and Birkett 1996). toxicity may result unless care is exercised (such as closely checking blood levels or lowering substrate doses in anticipation of the interaction). 2C9.

1A2. Spina et al. 1995). 1999). 2000). 1A2. or with an appreciation that an inhibitor is present.6 Drug–Drug Interaction Primer Example: Paroxetine Is Added to Nortriptyline Nortriptyline is a 2D6 substrate (Sawada and Ohtani 2001. 2003). The addition of paroxetine impairs the ability of 2D6 to metabolize nortriptyline. and phase II glucuronidation (Hachad et al. and phase II glucuronidation (Desai et al. 2D6. 2001. A decrease in levels of the substrate may result in a loss of efficacy of the substrate unless blood levels are followed and/or the substrate doses are increased in anticipation of the interaction. This increase in the available amounts of 3A4 and 1A2 (and possibly particular UGTs as well) leads to more efficient metabolism of the haloperidol and a resulting decrease in the blood level of haloperidol. If the substrate is titrated to specific blood levels or to therapeutic effect. 1998. Lucas et al. Toxicity may result unless appropriate caution is taken. 1999. the added nortriptyline generates a significantly higher nortriptyline blood level than would occur if the paroxetine was not already present (Leucht et al. 2000). 1999). 1998. Example: Nortriptyline Is Added to Paroxetine Nortriptyline is a 2D6 substrate (Sawada and Ohtani 2001. Pattern 3: An Inducer Is Added to a Substrate Adding an inducer to a substrate generally results in decreases in substrate levels. Parker et al. . Pattern 2: A Substrate Is Added to an Inhibitor Adding a substrate to an inhibitor may cause difficulties if the substrate has a low therapeutic index and is titrated according to preset guidelines that do not take into account the presence of an inhibitor. Venkatakrishnan et al. 1995). then toxicity is less likely to arise. leading to an increase in the blood level of nortriptyline (Leucht et al. Kudo and Ishizaki 1999). Venkatakrishnan et al. and haloperidol is metabolized by 3A4. and paroxetine is a 2D6 inhibitor (von Moltke et al. 2002. This may lead to clinical decompensation (Hesslinger et al. Yasui-Furukori et al. Because paroxetine inhibits the ability of 2D6 to metabolize nortriptyline. 1996). Example: Carbamazepine Is Added to Haloperidol Carbamazepine induces 3A4. and paroxetine is a 2D6 inhibitor (von Moltke et al.

and phase II glucuronidation (Hachad et al. and nortriptyline. Parker et al. 2001. leading to a significant decrease in the nortriptyline blood level (Leucht et al. and then discontinuing the inhibitor leads to a resumption of normal enzyme activity and generally results in decreases in levels of substrate and increased metabolite formation. 1999). 1999. Pattern 6: Reversal of Induction Coadministering a substrate and an inducer. Example: Haloperidol Is Added to Carbamazepine Carbamazepine induces 3A4. have been coadministered at appropriate doses. 1995). Pattern 5: Reversal of Inhibition Coadministering a substrate and an inhibitor. so as to achieve equilibria. 2D6. 2003). Yasui-Furukori et al. This may result in loss of efficacy of the substrate unless blood levels are followed and/or substrate doses are increased in anticipation of the reversal of inhibition. Kudo and Ishizaki 1999). 2D6 is then available to more efficiently metabolize the nortriptyline. and then discontinuing the inducer results in gradually (over 1–3 weeks) de- . 1A2. and haloperidol is metabolized by 3A4. thus generating a significantly lower haloperidol blood level at that haloperidol dose than would occur if carbamazepine was not already present (Hesslinger et al. Thus. Example: Paroxetine Is Discontinued in the Presence of Nortriptyline Paroxetine. resulting in a cessation of 2D6 inhibition. a 2D6 inhibitor (von Moltke et al. the presence of increased amounts of 3A4 and 1A2 (and possibly particular UGTs as well) leads to more efficient metabolism of the haloperidol. 1998. 2000). a 2D6 substrate (Sawada and Ohtani 2001. so as to achieve equilibria.Core Concepts 7 Pattern 4: A Substrate Is Added to an Inducer The addition of a substrate to an inducer may lead to ineffective dosing if preset dosing guidelines are followed that do not take into account the presence of an inducer. 2002. 1996). 1A2. then dosing is more likely to be effective. and phase II glucuronidation (Desai et al. Venkatakrishnan et al. possibly producing a subtherapeutic nortriptyline level and a loss of clinical efficacy. yielding an appropriate nortriptyline blood level and clinical efficacy. If the substrate is titrated to specific blood levels or to clinical effect. The paroxetine is then discontinued. or with an appreciation that an inducer is present. 1998. Lucas et al. when a given dose of haloperidol is administered. Spina et al.

not loss of efficacy. yielding an appropriate clozapine blood level and clinical efficacy. Armstrong SC. the clinical concerns are reversed. Miller R. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). leading to increased levels of substrate and decreased metabolite formation. UGTs. Sharma RP: Cytochrome enzyme genotype and the prediction of therapeutic response to psychotropics.. Ann Pharmacother 28:191–195. Clin Pharmacol Ther 71:141–152. Clin Pharmacokinet 37:177–193. Ptak LR. 2nd Edition. 2001 Batty KT. Zenon GJ 3rd. 2002 Cozza KL. hydrocodone. Tybring G. DC. and so forth. et al: The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects. P-Glycoproteins. Clin Pharmacokinet 29(suppl):20–25. Seymour MA: Phenytoin autoinduction. The Pattern 3 concern is toxicity. 1995 Brosen K: Drug interactions and the cytochrome P450 system: the role of cytochrome P450 1A2. Rodriguez-Barradas MC. REFERENCES Alam DA. This may result in substrate toxicity if the substrate has a low therapeutic index. et al: Fluconazole-induced symptomatic phenytoin toxicity. tramadol. The Exception When pro-drugs (e. Example: Smoking Is Discontinued in the Presence of Clozapine A two-pack-per-day cigarette smoker has been taking a stable dose of clozapine. 1998 Christensen M. Clozapine is a 1A2 substrate (Eiermann et al. 1997). 1994 Callaghan JT. cyclophosphamide) are the substrates in question. and cigarette smoking induces 1A2 (Schrenk et al. Washington. Zevin and Benowitz 1999). 1995 Cadle RM. 1999 Chetty M. not toxicity. possibly to a toxic degree (Zullino et al. et al: Olanzapine: pharmacokinetic and pharmacodynamic profile. resulting in a cessation of 1A2 induction. Bergstrom RF. The Pattern 1 concern is loss of efficacy. This leads to decreased metabolism of clozapine and a resulting increase in the blood level of clozapine. unless blood levels are followed and/or substrate doses are decreased in anticipation of the reversal of induction. Smoking is then discontinued. Br J Clin Pharmacol 39:305–311.8 Drug–Drug Interaction Primer creased amounts of available enzyme. Ther Drug Monit 20:60–62.g. Oesterheld JR: Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s. 1998. 2003 . Mihara K. Davis TM. 2002). Psychiatr Ann 31:715–722. American Psychiatric Publishing. Ilett KF.

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Mol Diagn 4:365–379. Ieiri I. 1998 Rasmussen BB. Backman JT. Psychopharmacology (Berl) 147:378–383. Graham R. Eur J Clin Pharmacol 53:361–367. et al: Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Tucker GT. et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. Ann Med Psychol (Paris) 153:140–143. et al: The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. Morike K. 2001 Parker AC. timolol. et al: Debrisoquine polymorphism and the metabolism and action of metoprolol. 1998 . Carroll K. et al: CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6. Ishizaki T: Pharmacokinetics of haloperidol: an update. Steimer W. Eur J Clin Pharmacol 54:735–740. Preston T. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. its role in psychopharmacology [in French]. Bouquet S. Ohtani H: Pharmacokinetics and drug interactions of antidepressive agents (in Japanese). et al: Involvement of CYP1A2 in mexiletine metabolism. Clin Pharmacokinet 37:435–456. Epilepsia 39:1317–1323. 1986 Leucht S. 1996 Nakajima M. Pritchard P. 1998 Niemi M. Birkett DJ: The use of caffeine as a metabolic probe for human drug metabolizing enzymes. propranolol and atenolol. 1998 Madan A. Pharmacotherapy 22:1001– 1006. Brosen K: Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro. Gaedigk A. Drug Metab Dispos 31:421–431. Bergstrom RF: A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism. Br J Clin Pharmacol 45:176– 178. Br J Clin Pharmacol 46:55–62. 1999 Lucas RA. et al: Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients. Nielsen TL. 1995 Lennard MS. Hackl HJ. Clin Pharmacol Ther 69:194–200.10 Drug–Drug Interaction Primer Kudo S. Perault MC. Silas JH. Neuvonen M. 1998 Sawada Y. 2002 Lamard L. et al: Cytochrome P450 2D6. Ereshefsky L. 1998 Miners JO. Eur J Clin Pharmacol 54:639–643. Xenobiotica 16:435–447. Gilfillan DJ. Nippon Rinsho 59:1539–1545. Kobayashi K. 2003 Mamiya K. 2001 Schrenk D. Shimamoto J. et al: Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test. Gen Pharmacol 27:245–249. 2000 Linder MW. 1999 Lam YW. Shimada N. Valdes R Jr: Pharmacogenetics in the practice of laboratory medicine. Brockmeier D.

and by quinidine and ketoconazole: a model system to predict drug interactions in vivo. J Pharmacol Exp Ther 268:1278–1283. Clin Pharmacokinet 36:425–438. et al: Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. 1993 Venkatakrishnan K. Int Clin Psychopharmacol 17:141–143. J Clin Psychopharmacol 15:125–131. 1991 von Moltke LL. 1999 Zhang ZY. 1999 von Bahr C. et al: Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Drug Metab Dispos 30:1102–1107. Kaminsky LS: Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. et al: Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype. 2002 . Eap CB. et al: Stereoselective hydroxylation of mexiletine in human liver microsomes: implication of P450IID6—a preliminary report. J Clin Pharmacol 39:567–577. 1995 Wietholtz H. 1995 Yasui-Furukori N. 2003 Zevin S. Greenblatt DJ. Marschall HU. Court MH. et al: The influence of rifampin treatment on caffeine clearance in healthy man. Mihara K. Broly F. Greenblatt DJ. 2002 Spina E. et al: Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochrome P450 enzymes in vitro: mechanism of drug interaction between TCAs and phenytoin. Kim MJ. 1996 Vandamme N. Pisani F. 1995 Zullino DF. Kondo T. Cotreau-Bibbo MM.Core Concepts 11 Shin JG. Libersa C. Nordin C. J Cardiovasc Pharmacol 21:77–83. Biochem Pharmacol 50:205–211. Clin Pharmacokinet 31:198–214. Movin G. Delessert D. Greenblatt DJ: Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs. Zysset T. Park JY. Clin Pharmacol Ther 49:234–240. von Moltke LL. J Hepatol 22:78–81. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. 1994 von Moltke LL. Benowitz NL: Drug interactions with tobacco smoking: an update. et al: Significant dose effect of carbamazepine on reduction of steady-state plasma concentration of haloperidol in schizophrenic patients. J Clin Psychopharmacol 23:435–440.

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the patient had not yet responded. so the paroxetine was further increased to 40 mg/day. including nortriptyline.Chapter 2 PSYCHIATRY CASE VIGNETTES PALPITATIONS A 55-year-old woman with refractory major depressive disorder had been maintained on nortriptyline (Pamelor). 20 mg/day.B. A nortriptyline level drawn several days earlier was 359 ng/mL. for 1 month. After 2 weeks. An electrocardiogram showed sinus tachycardia (114 beats/minute) with no evidence of conduction blockade (N. at which time she remained depressed and presented with the additional symptoms of dizziness and palpitations. so she treated this patient more aggressively than was typical for her. the patient was seen in consultation. are at least partial substrates of 2D6 (Sawada and Ohtani 2001). Sandson. 1995). August 1994). 100 mg/day. All tricyclic antidepressants (TCAs). The psychiatrist’s concern led her to add paroxetine (Paxil). Discussion This is an example of an inhibitor added to a substrate. Secondary-amine 13 . Paroxetine is a potent competitive inhibitor of 2D6 (von Moltke et al. generating a level of 90 ng/mL. Her psychiatrist was especially concerned about her deteriorating condition. Four weeks later. self-report.

and 1A2 all play potentially significant roles in the metabolism of tertiary-amine TCAs. 1999. 7-ethoxycoumarin. Hackl HJ. Sai Y.g. This case was slightly unusual in that a doubling of the trough nortriptyline level. Zhang and Kaminsky 1995).. The metabolism of tertiary-amine TCAs (e. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. Iselius L. The enzymes 2D6. rather than a 300% increase.. 1998. imipramine. Eur J Clin Pharmacol 44:445–450. et al: Polymorphic 2-hydroxylation of desipramine: a population and family study. Krausz KW. the ability of 2D6 to metabolize the nortriptyline was significantly impaired. would be more typical of this interaction (Leucht et al. clomipramine) is much more complex. Yang et al. Psychopharmacology (Berl) 147:378–383. Venkatakrishnan et al.14 Drug–Drug Interaction Primer TCAs (e. Prior to adding the paroxetine. 1996 Sawada Y. von Moltke LL. 2000). Court MH. Ohtani H: Pharmacokinetics and drug interactions of antidepressive agents (in Japanese). et al: Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4. Sawada and Ohtani 2001. Greenblatt DJ: Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs. a steady-state equilibrium had been established between the stable dosage of nortriptyline and the baseline activity of 2D6 in this individual. 2C19.g. manifested by moderate sinus tachycardia. 1993 Leucht S. 1999 . protriptyline) are preferentially metabolized by 2D6 and secondarily metabolized by 3A4 and 1A2 (Dahl et al. This led to a state of mild TCA toxicity. 1996. Flinois JP. resulting in a fourfold increase in the nortriptyline blood level. nortriptyline. Drug Metab Dispos 27:102–109. desipramine. 1998 Venkatakrishnan K. 3A4. 1999 von Moltke LL. Greenblatt DJ. Steimer W. von Moltke LL. 1999). Beaune P. even though there had been no change in the nortriptyline dosage. 1993. et al: The biotransformation of clomipramine in vitro: identification of the cytochrome P450s responsible for the separate metabolic pathways. 2000 Nielsen KK. amitriptyline. 1995 Yang TJ. Greenblatt DJ. 2001 Venkatakrishnan K. and imipramine metabolism. With the addition of the paroxetine. et al: Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients. References Dahl ML. Alm C. J Clin Psychopharmacol 15:125–131. et al: Eight inhibitory monoclonal antibodies define the role of individual P450s in human liver microsomal diazepam. Nippon Rinsho 59:1539–1545. J Pharmacol Exp Ther 277:1659–1664. and the specifics vary with each individual tertiary-amine TCA (Nielsen et al. J Clin Pharmacol 38:112–121. J Clin Pharmacol 39:567–577. Venkatakrishnan et al.

10 mg qhs. and mild memory impairment. 1. urinary retention. urinary retention. and alcohol dependence in full remission was being stably maintained on haloperidol (Haldol). the patient experienced new-onset blurring of his vision. both of his parents died from medical causes. . Discussion This is an example of an inhibitor added to a substrate. His psychiatrist hoped to alleviate these panic attacks by adding paroxetine (Paxil). The increased benztropine level led to the emergence of several anticholinergic symptoms (blurry vision due to mydriasis. Kaminsky LS: Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. 1995) inhibit benztropine’s metabolism. Within 5 days.000 mg bid. he could not remember what day it was or whether it was morning or evening. After taking a nap and waking in the early evening. this led to the emergence of frequent and debilitating panic attacks. 20 mg qhs. to the patient’s regimen. His haloperidol and divalproex levels were essentially unchanged and in the normal range. and mild confusion). thus inducing another severe panic attack. and divalproex sodium (Depakote).Psychiatry Case Vignettes 15 Zhang ZY. Biochem Pharmacol 50:205–211. Over the previous 2 years. The psychiatrist told the patient to stop taking the paroxetine and sent him to have blood levels drawn for his medications. 2 mg bid. On receiving this result. the psychiatrist held the patient’s benztropine. and there have been several documented instances that suggest that 2D6-inhibiting selective serotonin reuptake inhibitors such as paroxetine (von Moltke et al. alleviated his haloperidol-induced tremor and stiffness without causing any further side effects. even though the benztropine dosage had not been changed. The addition of paroxetine to the regimen impaired the ability of 2D6 to efficiently metabolize the benztropine. Benztropine (Cogentin). bipolar type. Benztropine is believed to be a 2D6 substrate. and his anticholinergic symptoms abated over the next 3 days (Armstrong and Schweitzer 1997). but his benztropine level (no baseline) was 42 ng/mL (levels >25 ng/mL are considered toxic) (Specialty Laboratories 2001). which led to an increase in the blood level of benztropine. the psychiatrist declined to use benzodiazepines to avoid rekindling the patient’s alcohol use. 1995 PANICKED AND CONFUSED A 35-year-old man with long-standing schizoaffective disorder.

he was noted by facility staff to be more cranky and irritable.16 Drug–Drug Interaction Primer References Armstrong SC. The addition of paroxetine potently inhibited 2D6 (von Moltke et al. Vitamin E was also added and titrated to a dosage of 2. His internist had previously prescribed diltiazem (Cardizem). One day. 2001 von Moltke LL. a potent 3A4 inhibitor (Sutton et al. The psychiatrist opted to start the patient on paroxetine (Paxil). Donepezil is metabolized primarily by 2D6 and secondarily by 3A4 (Eisai 2000). the addition of paroxetine increased the blood level of donepezil. They also obtained a consultation with a psychiatrist. and initiated a trial of citalopram (Celexa). an acetylcholinesterase inhibitor. 1995 CRANKY AND CRAMPY An 86-year-old man with Alzheimer’s dementia was experiencing increasing difficulties living independently. which the patient was taking on a chronic basis for control of his hypertension. Over the next 2 months. 1997 Specialty Laboratories: Directory of Services. Schweitzer SM: Delirium associated with paroxetine and benztropine combination. Thus. Santa Monica. Discussion This is an example of an inhibitor added to a substrate. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. Court MH. which led to the cholinergic side effects of cramping and diarrhea. waited 2 weeks. hopelessness.000 IU/day. and sense of abandonment by his family as well as decreased sleep and appetite. His family orchestrated his transition to an assisted-living facility. 1995). prevented 3A4 from serving as an effective accessory metabolic pathway for donepezil. . Am J Psychiatry 154:581–582. the patient revealed his resentment. CA. In the week after starting the paroxetine. In the interview with the patient. Greenblatt DJ. The psychiatrist then stopped the paroxetine. he became so frustrated about receiving turkey for lunch rather than roast beef that he hurled his lunch tray across his room. J Clin Psychopharmacol 15:125–131. which the patient tolerated without difficulty. 10 mg/day for 3 days and 20 mg/day thereafter. the patient experienced increasingly distressing abdominal cramping and diarrhea. 1997). The psychiatrist was consulted again. 2001. thus impairing its ability to efficiently metabolize the donepezil. who started the patient on donepezil (Aricept) and titrated his dosage to 10 mg/day. The presence of diltiazem. Specialty Laboratories.

the patient and his psychiatrist decided to try the free samples of citalopram (Celexa) that were available at the clinic in the place of the paroxetine. and he tolerated this addition without significant side effects. Desmethylclomipramine is clomipramine’s primary metabolite via demethylation by 2C19 and 3A4. which led to the loss of his insurance coverage. Discussion This is an example of reversal of inhibition. He was able to maintain gainful employment only by surviving on 3–4 hours of sleep each night. He would routinely spend 4 or more hours each day cleaning himself and straightening his apartment. and 2D6. As such. paroxetine’s competitive inhibition of 2D6 . Nadin L. Over the next 6 weeks. The patient did well on this regimen for 2 years. 2000 Sutton D. After 4 days. et al: Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. although not as severe as they had been before the addition of the clomipramine. 1997 von Moltke LL. J Clin Psychopharmacol 15:125–131. No side effects emerged. NJ. Court MH. Teaneck. titrated to a dosage of 60 mg/day. A clomipramine blood level (reported as clomipramine + desmethylclomipramine) drawn 1 week later was in the normal range.Psychiatry Case Vignettes 17 References Eisai: Aricept (package insert). Clomipramine is a tertiary-amine tricyclic antidepressant whose metabolism depends most on the intact functioning of 2C19. the patient began to experience significant improvement in his OCD symptoms. he then lost his job during a flurry of downsizing. with 1A2 serving as a secondary enzyme. the dosage was increased to 50 mg/day. Paroxetine is a potent competitive inhibitor of 2D6 (von Moltke et al. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. Greenblatt DJ. Eisai. J Pharmacol Exp Ther 282:294–300. leading him to a state of exhaustion by each Friday. Butler AM. 3A4. 1995). but within 1 month the patient’s cleaning rituals were significantly worse. In view of his financial difficulties. The decision was made to add clomipramine (Anafranil) at an initial dosage of 25 mg/day. 2D6 catalyzes hydroxylation of both clomipramine and desmethylclomipramine (Nielsen et al. 1996). 1995 THE POTENTIAL PERILS OF FRUGALITY A 19-year-old man with newly diagnosed obsessive-compulsive disorder (OCD) had experienced only a marginal response to paroxetine (Paxil). However.

et al: The biotransformation of clomipramine in vitro: identification of the cytochrome P450s responsible for the separate metabolic pathways. Thus. This led to a significant loss of clinical efficacy in this case. 2004 Nielsen KK. the presence of paroxetine enabled a relatively low dosage of clomipramine to produce a therapeutic response (Skjelbo and Brosen 1998). 2001 Forest Pharmaceuticals: Celexa (package insert). with the replacement of paroxetine by citalopram. St. This prompted the psychiatrist to recheck the amitriptyline + nortriptyline blood level. As an attempt at augmentation. . Ugeskr Laeger 160:5665–5666. personal communication. J Clin Psychopharmacol 15:125–131. Flinois JP. May 2002). Forest Pharmaceuticals. and blurry vision.18 Drug–Drug Interaction Primer was able to significantly impair the metabolism of both clomipramine and desmethylclomipramine. Her psychiatrist opted to try amitriptyline (Elavil). titrated to a dosage of 200 mg/day. leading to an increase in this total blood level. Her amitriptyline + nortriptyline blood level was 732 ng/mL (M. Levinson. including trials of several selective serotonin reuptake inhibitors. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. MO. titrating to a dosage of 200 mg bid. venlafaxine (Effexor). however. 1996 Skjelbo EF. and mirtazapine (Remeron). Naranjo CA: Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. Brosen K: [Interaction between paroxetine and clomipramine as a possible reason for admission to a department of internal medicine]. is a much less potent inhibitor of 2D6 (Brosen and Naranjo 2001. 1998 von Moltke LL. At this dosage. the psychiatrist added bupropion (Wellbutrin SR). Eur Neuropsychopharmacol 11:275–283. dry mouth. Greenblatt DJ. as well as to obtain an electrocardiogram. She remained on this dosage for 6 weeks. Over the next 10 days. Court MH. 1995 ANERGY THROUGH SYNERGY A 27-year-old woman failed to respond to numerous sequential antidepressant monotherapy trials. References Brosen K. Beaune P. with the result that the clomipramine + desmethylclomipramine level declined. J Pharmacol Exp Ther 277:1659–1664. Forest Pharmaceuticals 2004). Citalopram. The electrocardiogram revealed a sinus tachycardia of 128 beats per minute with a change in QTc interval from 436 msec to 509 msec. her blood level of amitriptyline + nortriptyline (amitriptyline’s primary metabolite) was 185 ng/mL. the patient experienced increasing lethargy. nefazodone (Serzone). clomipramine’s metabolism was being much less robustly inhibited. Thus. Louis. without discernible improvement.

However. Tracy TS. R. One year later. et al: Inhibition of CYP2D6 activity by bupropion. which led to an almost fourfold increase in the amitriptyline + nortriptyline blood level. J Clin Pharmacol 38:112–121. her schedule became so hectic that she intermittently forgot to take her citalopram. von Moltke LL. Thus. Bupropion is a relatively potent 2D6 inhibitor (Kotlyar et al. 2D6 catalyzes hydroxylation of both amitriptyline and nortriptyline (Venkatakrishnan et al. specifically . 1998 Venkatakrishnan K. she again became pregnant. She and her psychiatrist decided to switch to the once-per-week preparation of fluoxetine (Prozac). A similar effect has been observed when bupropion has been added to imipramine (Tofranil). resulting in elevations of imipramine + desipramine blood levels (J. 2005. and she responded well to a dosage of 90 mg/week. GlaxoSmithKline. GlaxoSmithKline 2001). and 2D6. Research Triangle Park. von Moltke LL. 1998. References GlaxoSmithKline: Wellbutrin (package insert). 3A4. However. for her recurrent major depressive disorder. This state of tricyclic toxicity caused the changes in cardiac conduction described in the case. personal communication.Psychiatry Case Vignettes 19 Discussion This is an example of an inhibitor added to a substrate. Greenblatt DJ: Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs. J Clin Psychopharmacol 25:226–229. Amitriptyline is a tertiary-amine tricyclic antidepressant whose metabolism depends most on the intact functioning of 2C19. the addition of bupropion significantly impaired the ability of 2D6 to contribute to the metabolism of amitriptyline and nortriptyline. J Clin Pharmacol 39:567–577. following the birth of this child. and she continued taking her fluoxetine throughout the pregnancy. May 2002). with 1A2 serving as a secondary enzyme. Greenblatt DJ. 2001 Kotlyar M. 2005 Venkatakrishnan K. NC. Brauer LH. 1999 POSTPARTUM PSYCHOSIS A 35-year-old mother of two children had responded well to a regimen of citalopram (Celexa). 1999). 20 mg/day. Oesterheld. Nortriptyline is amitriptyline’s primary metabolite via demethylation by 2C19 and 3A4. she experienced postpartum depression with prominent psychotic features. et al: Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4. following the birth of her second child.

” painful spasms of her thigh muscles. then 200 mg/day of thioridazine generated a significantly higher blood level (probably by a factor of two to four) because of the reduction in 2D6’s ability to metabolize the thioridazine.” During previous psychotic depressions. 2000 Stevens JC. Thioridazine is a 2D6 substrate (von Bahr et al. 1991 . which the patient tolerated without difficulty. NJ. Nordin C. the thioridazine package insert has recently been modified. Clin Pharmacol Ther 49:234–240. and frequent light-headedness.C. per the patient’s firm wishes. 200 mg/day was an effective and tolerable dosage. When thioridazine was used in the past with antidepressants that did not significantly inhibit 2D6 (such as citalopram). 200 mg/day. It now states that thioridazine should not be prescribed with 2D6 inhibitors because of the risk of thioridazine blood level increases. Discussion This is an example of a substrate added to an inhibitor. However. she had taken thioridazine (Mellaril). et al: Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype. The psychiatrist discontinued the thioridazine. Novartis Pharmaceuticals. These higher concentrations of thioridazine then generated the symptoms of acute dystonia and orthostatic hypotension described by the patient. The patient required benztropine (Cogentin) to control these symptoms for the next 2 days. a dosage that had been both effective and well tolerated. J Pharmacol Exp Ther 266:964–971. East Hanover. and fluoxetine is a strong 2D6 inhibitor (Stevens and Wrighton 1993). within 5 days. after which they abated. Movin G. personal communication. May 2002). 1993 von Bahr C. References Novartis Pharmaceuticals: Mellaril (package insert). she complained about having a “thick tongue. Armstrong. when fluoxetine significantly impaired the ability of 2D6 to efficiently metabolize the thioridazine. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. 1991). predisposing to prolongations of the QTc interval and subsequent arrhythmias (Novartis Pharmaceuticals 2000). and which proved helpful for her nihilistic delusions and associated hallucinations over the next 2 weeks (S.20 Drug–Drug Interaction Primer nihilistic delusions of worthlessness and auditory hallucinations telling her that “the children will be better off without you. Although it is not a central issue in this case. Her psychiatrist admitted her to the local day hospital program and again restarted her on thioridazine. However. Thioridazine was restarted and titrated to a dosage of 75 mg qhs. 200 mg/day.

the blood levels of secondaryamine TCAs (nortriptyline. but not 3A4 inhibitors. amitriptyline. whereupon he discontinued the desipramine and ordered a stat electrocardiogram and desipramine blood level. Soon before his transition to routine outpatient care. dry mouth. he chose to present for treatment at a local dual-diagnosis day hospital. This toxic desipramine level resulted in the patient’s tachycardia. his methadone was restarted at the prior dosage of 60 mg/day. thus leading to a significant increase in the desipramine blood level (Maany et al. 60 mg/day. Over the ensuing week. . He reported these symptoms and his rapidly increasing lethargy to his psychiatrist. After being confronted by several family members. Desipramine is primarily a substrate of 2D6 (Dahl et al. The introduction of methadone significantly impaired the ability of 2D6 to metabolize the desipramine. which predisposed him to develop a fever and severe lethargy during a hot summer week. and more general anhydrosis. and doxepin) may be elevated by the addition of either 2D6 or 3A4 inhibitors. The psychiatrist started him on desipramine. even though the dosage had not been further increased. and a past history revealed prior depressive episodes with a good past response to desipramine (Norpramin). desipramine. clomipramine. sedation. which generated a desipramine blood level of 154 ng/mL. Also. he was sweating very little. as are other secondary-amine tricyclic antidepressants (TCAs). and had again begun abusing speedball (intravenous heroin and cocaine).and tertiary-amine TCAs. The psychiatrist found that the patient had a temperature of 101°F.Psychiatry Case Vignettes 21 DRY HEAT A 27-year-old man with polysubstance dependence had discontinued his use of methadone (Dolophine). It is worth noting that whereas the blood levels of tertiary-amine TCAs (imipramine. this was a very hot time of the summer. 1993). Discussion This is an example of an inhibitor added to a substrate. he experienced increasing sedation and dry mouth. and protriptyline) will generally be increased by the addition of 2D6 inhibitors. 1993). with no significant side effects. whereas the demethylation performed by 3A4 is much less crucial to the metabolism of secondary-amine TCAs. Methadone is a moderately strong inhibitor of 2D6 (as well as 3A4) (Wu et al. The psychiatrist there diagnosed him with depressive disorder not otherwise specified. This is because the hydroxylation performed by 2D6 is quite important to the metabolism of both secondary. The electrocardiogram showed sinus tachycardia of 110 beats per minute and a desipramine blood level of 393 ng/mL. titrating the dosage to 200 mg/day. and he found that despite feeling especially hot. 1989). The patient tolerated the desipramine quite well.

Alprazolam is a 3A4 substrate. 1988. Otton SV. Carbamazepine is an inducer of multiple P450 enzymes. Dhopesh V. 1993 SURPRISING SEDATION A 22-year-old woman carried the diagnoses of both bipolar I disorder and panic disorder. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. 800 mg/day. she and her psychiatrist decided to quickly discontinue her carbamazepine and begin a trial of lithium. One of her routine complete blood counts revealed an evolving leukopenia. With the discontinuation of the carbamazepine. Her symptoms had been well controlled on a regimen of carbamazepine (Tegretol). yielding higher alprazolam blood levels and subsequent oversedation. 1996. Spina et al. the alprazolam was titrated to stable clinical effect (control of panic attacks without sedation) at a (higher) dosage that took into account a stable degree of 3A4 induction by carbamazepine (Arana et al. Her psychiatrist decreased her alprazolam to 1. 4 mg/day. 1988 . 2004). within 3 weeks of discontinuing the carbamazepine.5 mg/ day. However. Ucar et al. Molloy M. 1989 Wu D. Sproule BA. Iselius L. When carbamazepine and alprazolam were coadministered. J Clin Psychiatry 49:448–449. she experienced marked sedation. 1993 Maany I. References Arana GW. The resulting decrease in available 3A4 led to less active metabolism of the alprazolam. Alm C.22 Drug–Drug Interaction Primer References Dahl ML. and this dosage was well tolerated. Am J Psychiatry 146:1611–1613. as are the other triazolobenzodiazepines (triazolam. Arndt IO. Eur J Clin Pharmacol 44:445–450. Br J Clin Psychopharmacol 35:30–34. midazolam. specifically including 3A4 (Arana et al. Initial titration of the lithium to a dosage of 900 mg/day took place without incident. which continued to effectively prevent panic attacks and which she tolerated without sedation (Pies 2002). and alprazolam (Xanax). 2000). et al: Increase in desipramine serum levels associated with methadone treatment. Epstein S. which interfered with her ability to do her job. Discussion This is an example of reversal of induction. there was a reversal of 3A4 induction. et al: Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone. and estazolam) (Dresser et al. After discussing risks and benefits. 1988). et al: Polymorphic 2-hydroxylation of desipramine: a population and family study.

Eur J Clin Pharmacol 59:879– 882. 1997 Greenblatt DJ. Roughly 3 weeks after reaching a fluoxetine dosage of 20 mg/day. May 2002. Luurila H. References Azaz-Livshits TL. Nifedipine is a 3A4 substrate (Iribarne et al. 1999 . He was also taking nifedipine (Procardia) for his hypertension. von Moltke et al. His psychiatrist decided to discontinue the mirtazapine and begin a trial of fluoxetine (Prozac). Pharmacopsychiatry 30:274–275. Clin Pharmacokinet 38:41–57. it was 80/50 mm Hg (Azaz-Livshits and Danenberg 1997). et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. 30 mg/day. J Clin Psychopharmacol 19(suppl):23S–35S. 1997). However. the patient attempted to get out of bed. His son heard him fall and found him lying on his back on the floor. 2004 HORIZONTAL A 79-year-old man with long-standing anxious depression was undergoing a trial of mirtazapine (Remeron). Pisani F. Psychiatric Times. At the patient’s baseline. norfluoxetine (Greenblatt et al. 1995). pp 48–51 Spina E. metabolism. and when the paramedics took the man’s supine blood pressure. whereupon he had a syncopal episode. This resulted in an increase in the blood level of nifedipine. the introduction of fluoxetine led to a significant decrease in the ability of 3A4 to efficiently metabolize nifedipine. The son called an ambulance. the blood level of nifedipine appropriately controlled his hypertension without producing orthostasis. Discussion This is an example of an inhibitor added to a substrate. 1996 Ucar M. et al: Human cytochromes and some newer antidepressants: kinetics. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. even though the dosage of nifedipine had not been changed. von Moltke LL. 2000 Pies R: Cytochromes and beyond: drug interactions in psychiatry. Danenberg HD: Tachycardia.Psychiatry Case Vignettes 23 Dresser GK. 1999. and drug interactions. The patient was not able to tolerate the mirtazapine because of sedation. Spence JD. Clin Pharmacokinet 31:198–214. and led to the orthostasis-induced syncopal episode. orthostatic hypotension and profound weakness due to concomitant use of fluoxetine and nifedipine. and fluoxetine produces moderate inhibition of 3A4 through its active metabolite. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Harmatz JS. Neuvonen M.

et al: Interaction of methadone with substrates of human hepatic cytochrome P450 3A4. which proved effective for the panic attacks without producing excessive sedation. Discussion This is an example of an inhibitor added to a substrate. 2000). and concentration. Court MH.5 mg tid). Toxicology 117:13–23. She began to experience increasing dysphoria and anhedonia. Her alprazolam was then restarted at half the previous dosage (0. 1996). A halving of the alprazolam dosage compensated for this inhibition. the patient began to experience marked sedation that was interfering with her ability to study. Bardou LG. Numerous separation issues and impending life changes. 1995 SLEEPY A 21-year-old college student was taking alprazolam (Xanax). there was a reemergence of her panic attacks. Alprazolam is a 3A4 substrate (Dresser et al. which led to a resolution of the sedation. Nemeroff CB: 2002 guide to psychotropic drug interactions. leading to therapeutic efficacy without oversedation. for panic disorder.24 Drug–Drug Interaction Primer Iribarne C. Within 2 days of reaching a dosage of only 100 mg bid. poor sleep. additive receptor effects (pharmacodynamic effects) may have also contributed to this interaction. and heightened generalized anxiety—which led the patient and her psychiatrist to consider adding an antidepressant to her regimen. Greene et al. They decided to try nefazodone (Serzone). 1 mg tid. and nefazodone is a strong competitive inhibitor of 3A4 (von Moltke et al. as well as final examination pressures. led to an especially stressful 6 weeks before her planned graduation. Prim Psychiatry 9:28–57. appetite. even though the alprazolam dosage had initially remained constant (DeVane and Nemeroff 2002. The psychiatrist discontinued the alprazolam. The addition of nefazodone led to a significant reduction in the ability of 3A4 to efficiently metabolize alprazolam. Greenblatt DJ. Dreano Y. J Clin Psychopharmacol 15:125–131. 1995). 2002 . et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. This resulted in a significant increase (roughly doubling) of the blood level of alprazolam. 1997 von Moltke LL. Because both of these agents are independently sedating. but after 3 days. which provided good relief and which she tolerated without difficulty. References DeVane CL.

but not hepatic. Carbamazepine is primarily a 3A4 substrate.Psychiatry Case Vignettes 25 Dresser GK. The psychiatrist ordered a carbamazepine level. Grapefruit juice is an inhibitor of hepatic 1A2 (Fuhr 1998. et al: Coadministration of nefazodone and benzodiazepines. The addition of grapefruit juice to the patient’s diet impaired the ability of 1A2 and. Clin Pharmacokinet 38:41–57. Salazar DE. the psychiatrist suggested skipping the next two doses of carbamazepine and switching from grapefruit juice to water. 1996. 1996 BITTER FRUIT A 26-year-old man with bipolar I disorder had maintained acceptable control on a regimen of lithium (Eskalith). Discussion This is an example of an inhibitor added to a substrate. 0. 11 µg/mL). . J Pharmacol Exp Ther 276:370–379. Greenblatt DJ. This carbamazepine–grapefruit juice interaction is likely mediated both through P450 enzyme inhibition (3A4 [mostly] and 1A2) and through inhibition of the P-glycoprotein transport system. Fuhr et al. tremor. and significantly nauseated. 400 mg bid (most recent blood level. Harmatz JS. 2B6. which was found to be 17. and sedation. with 1A2. 1993) and a moderate inhibitor of intestinal. he became increasingly sedated. J Clin Psychopharmacol 15:399–408. After discussing the patient’s recent dietary changes. 3A4 as well (Fuhr 1998. 1998).5 µg/mL. This increase in the carbamazepine blood level led to the patient’s new nausea and vomiting. mildly tremulous.8 mEq/L). 2002. 1. III: a pharmacokinetic interaction study with alprazolam. more importantly. As it happens. Spence JD. In his ongoing efforts to adopt a healthier lifestyle. 2000 Greene DS. 2C8/9. thus raising the blood level of carbamazepine even though the dosage had not been changed (Garg et al. 2E1. Spina et al. 1998). 1995 von Moltke LL. After vomiting twice in 2 days. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. He et al. et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. 2004). he decided to stop drinking sodas and he began to consume more than 16 ounces per day of grapefruit juice. Dockens RC. he complained to his psychiatrist. intestinal 3A4 to contribute to the metabolism of carbamazepine. and carbamazepine (Tegretol). Staines et al. and phase II metabolism (uridine 5′-diphosphate glucuronosyltransferase 2B7) making minor contributions to carbamazepine’s metabolism (Pearce et al.200 mg/day (most recent blood level. Over the next week.

Clement RP. on CYP1A2 dependent metabolism of caffeine in man. 1996 Staines AG. there is evidence that grapefruit juice can significantly elevate the blood levels of calcium-channel blockers and cyclosporine (Fuhr 1998). Even though the interaction in this case was more bothersome than dangerous. Drug Metab Dispos 30:1170–1179. 2001 . possibly with dire consequences. Kumar N. et al: Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy. just as one would inquire about any other agent on a medication list. 1998 He K. Hayes RN. grapefruit juice also raises carbamazepine levels by impairing the ability of P-glycoprotein to extrude carbamazepine from enterocytes back into the gut lumen. where it would then be excreted rather than absorbed. 2004 Wang EJ. It is also prudent to avoid combining grapefruit juice with clozapine or with tertiary-amine tricyclics.and 3-hydroxylated metabolites. References Fuhr U: Drug interactions with grapefruit juice: extent. Neuroreport 12:3557–3560. Klittich K. Fedrowitz M. Concerns regarding unregulated grapefruit juice consumption have led some astute clinicians to have it removed from hospital menus. a component of grapefruit juice. I: characterization of human cytochromes P450 responsible for the formation of 2. Because grapefruit juice is obviously not a regulated substance. probable mechanism and clinical relevance. Clin Pharmacokinet 31:198–214. Pisani F. Br J Clin Pharmacol 35:431–436. 2001). Burchell B: N-Glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. 2001 Spina E. et al: Inactivation of cytochrome P450 3A4 by bergamottin. Vakkalagadda GR. 1998 Pearce RE.26 Drug–Drug Interaction Primer carbamazepine is a substrate of the P-glycoprotein transporter (Potschka et al. Staib AH. naringenin. in addition to 3A4 and 1A2 inhibition. Leeder JS: Pathways of carbamazepine bioactivation in vitro. 2002 Potschka H. et al: Inhibitory effect of grapefruit juice and its bitter principal. 1998 Fuhr U. Casciano CN. J Pharmacol Exp Ther 311:1131–1137. Drug Saf 18:251–272. Thus. Bhargava VK. 2001). et al: Inhibition of P-glycoprotein transport function by grapefruit juice psoralen. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Loscher W: P-glycoprotein and multidrug resistance– associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. and grapefruit is an inhibitor of this transporter (Wang et al. Iyer KR. Chem Res Toxicol 11:252–259. Coughtrie MW. 1993 Garg SK. Pharm Res 18:432–438. it is important to ask specifically about patient consumption of grapefruit or grapefruit juice. Clin Pharmacol Ther 64:286–288.

3A4 resumed its baseline (higher) level of activity. S. He reported that he was sleeping only 4–5 hours each night and that this was making him “miserable. loss of appetite. Pimozide is a 3A4 substrate (Desta et al. With the discontinuation of the nefazodone. even though the dosage had not been changed (Dresser et al.” His psychiatrist decided to add nefazodone (Serzone). and insomnia. 2000. Spence JD. Over the past 2 months. which was titrated to a dosage of 400 mg/day. 1999 Dresser GK.Psychiatry Case Vignettes 27 INSOMNIA A 28-year-old man with schizoaffective disorder had remained free of auditory hallucinations and paranoid delusions while taking a regimen of pimozide (Orap).” The psychiatrist discontinued the nefazodone. 1996). 2000 . leading to an increase in the blood level of pimozide. Over the next week. Gate Pharmaceuticals 1999). Kerbusch T.L. the akathisia remitted and his electrocardiogram results normalized. he had developed progressive dysphoria. May 2002). References Desta Z. Soukhova N. a remission of the akathisia. J Pharmacol Exp Ther 285:428–437. and divalproex sodium (Depakote).250 mg/day. personal communication. 6 mg/day. Armstrong. and nefazodone is a strong competitive inhibitor of 3A4 (von Moltke et al. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Within 1 week of discontinuation of the nefazodone. This increased blood level of pimozide resulted in new-onset akathisia and QTc prolongation on his electrocardiogram. Cozza. and a normalization of the electrocardiographic results (K. et al: Identification and characterization of human cytochrome P450 isoforms interaction with pimozide. Discussion This is an example of an inhibitor added to a substrate. 1. Kerbusch T. Flockhart DA: Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). anergy. Clin Pharmacol Ther 65:10–20.C. The patient’s QTc interval had elongated from 425 msec to 510 msec. 1998 Desta Z. 1999). Clin Pharmacokinet 38:41–57. the patient displayed severe restlessness and he reported the odd sensation that his heart was “fluttering. and this led to a return of the pimozide blood level back to its (lower) baseline. but he did check a stat electrocardiogram. The addition of nefazodone impaired the ability of 3A4 to efficiently metabolize the pimozide. 1998.

. DUB . Harmatz JS. May 2002. 1999 von Moltke LL. 240 mg/day. et al: Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil. . He developed erectile dysfunction and chronic sleep difficulties on this regimen. The addition of the nefazodone impaired the ability of 3A4 to efficiently metabolize the verapamil (a calcium-channel blocker). for the past 2 years. Korzekwa KR. Gonzalez FJ. Sellersville. et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. After discussing the risks. Gate Pharmaceuticals. and verapamil (Calan SR). pp 48–51 Tracy TS. LUB . This led to an increase in the blood level of verapamil. During the ambulance ride. This state of verapamil toxicity created a dangerous condition in the form of second-degree atrioventricular heart block. during an especially engaging episode of Law and Order. and he met with his psychiatrist to change his antidepressant selection. She called 911. and the emergency medical team transported him to the nearest emergency room. Greenblatt DJ. A 48-year-old lawyer diagnosed with anxious depression and hypertension had been maintained on citalopram (Celexa).28 Drug–Drug Interaction Primer Gate Pharmaceuticals: Orap (package insert). and nefazodone is a strong competitive inhibitor of 3A4 (von Moltke et al. Verapamil is a 3A4 substrate (Tracy et al. . benefits. the patient and his psychiatrist decided to taper and discontinue the citalopram and begin a trial of nefazodone. J Pharmacol Exp Ther 276:370–379. . 1996 . Br J Clin Pharmacol 47:545–552. . and the differing side-effect profiles. Discussion This is an example of an inhibitor added to a substrate. . PA. Psychiatric Times. even though the dosage had not been changed. 1996). he experienced increasing dizziness when rising from a sitting or lying position. he abruptly passed out and his wife was unable to revive him. One week later. 1999 . the heart monitor showed the presence of second-degree atrioventricular heart block with a ventricular rate of 41 beats per minute and a blood pressure of 70/30 mm Hg (Pies 2002). 40 mg/day. In the last week of this titration schedule. References Pies R: Cytochromes and beyond: drug interactions in psychiatry. The patient’s nefazodone was titrated to a dosage of 500 mg/day over the course of 3 weeks. 1999).

Zolpidem is principally a substrate of 3A4 (von Moltke et al. Greenblatt DJ. J Pharmacol Exp Ther 276:370–379. personal communication. et al: Human cytochromes and some newer antidepressants: kinetics. 1995). May 2002). One night when he was having trouble falling asleep. 1999. von Moltke LL. Indinavir is a strong 3A4 inhibitor (Iribarne et al. Harmatz JS. The patient lived with his parents and sister. the presence of the dual 3A4 inhibitors very strongly interfered with 3A4’s ability to efficiently metabolize the zolpidem.L. He subsequently slept more than 15 hours and seemed “drugged” for the rest of the day. 1999). et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. norfluoxetine. J Clin Psychopharmacol 19(suppl):23S–35S. Carlhant D. and his ruminations about these problems were leading to persistent-onset insomnia. Several months ago. et al: Inhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors. Greenblatt DJ. HIV-positive man with chronic depression had responded well to fluoxetine (Prozac). he began taking indinavir (Crixivan). This led to a much higher blood level of zolpidem than would have been expected at this dosage. Cozza. 1996 STEALING SISTER’S SLEEPERS A 36-year-old. the typical 800 mg) every 8 hours. he sneaked into his sister’s bathroom and took one of her 10-mg tablets of zolpidem (Ambien). is a moderate 3A4 inhibitor (Greenblatt et al. The patient took a dose of zolpidem that would be expected to produce an average amount of sleep in a young man. for the past 5 years. 1999 Iribarne C. with the result that the patient slept for an extended period and experienced substantial residual daytime sedation. 1998). Discussion This is an example of a substrate added to two inhibitors. with no residual daytime sedation. metabolism. as one of his HIV medications. and fluoxetine’s active metabolite. Court MH. von Moltke et al. Over the past month.Psychiatry Case Vignettes 29 von Moltke LL. Drug Metab Dispos 26:257–260. and drug interactions. 1998 von Moltke LL. 600 mg (vs. 20 mg/day. References Greenblatt DJ. he was having more difficulties at his job. Harmatz JS. J Clin Psychopharmacol 15:125–131. Berthou F. 1995 . neither of which was appreciated at his job (K. However.

Br J Clin Pharmacol 48:89–97. she noticed that she had gained 10 pounds. Topiramate has been found to decrease blood levels of ethinylestradiol by up to 30% (Rosenfeld et al. 1999 A WEIGHTY MATTER A 27-year-old woman with a history of bipolar I disorder and bulimia nervosa was taking olanzapine (Zyprexa). Oesterheld. Life Sci 47:1981– 1988.000 mg/day (blood level. Fundam Clin Pharmacol 14:301–319. Although the patient did not lose weight. Greenblatt DJ. 95 µg/mL) after a recent psychiatric hospitalization. Epilepsia 38:317–323. personal communication. May 2002). even though the dosage of ethinylestradiol had remained unchanged throughout. This decline in the ethinylestradiol component of the patient’s oral contraceptive led to her episode of breakthrough bleeding. resulting in a decrease in the blood level of the ethinylestradiol. 2000 Guengerich FP: Metabolism of 17 α-ethinylestradiol in humans. 1. Doose DR.R. and divalproex sodium (Depakote). Six weeks later. chemical inhibitors. She also was taking an oral contraceptive that contained ethinylestradiol. She complained to her psychiatrist at length about this weight gain. and in vivo correlations. The psychiatrist rather reluctantly added topiramate (Topamax). 1990 Rosenfeld WE. She did not experience any difficulties with cognition or paresthesias. References Benedetti MS: Enzyme induction and inhibition by new antiepileptic drugs: a review of human studies. et al: Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. 1997). titrating up to a dosage of 200 mg/day. Ethinylestradiol is a 3A4 substrate (Guengerich 1990). One month after discharge. Walker SA. Discussion This is an example of an inducer added to a substrate. 10 mg qhs. 1997 . the patient was surprised to discover that she was having breakthrough bleeding at an irregular time in her cycle (J. The addition of topiramate led to an increase in the amount of 3A4 that was available to metabolize the ethinylestradiol. and topiramate is a 3A4 inducer (Benedetti 2000). Granda BW. et al: Zolpidem metabolism in vitro: responsible cytochromes.30 Drug–Drug Interaction Primer von Moltke LL. ultimately threatening to stop all of her medications unless he addressed this issue to her satisfaction. she did not gain any further weight.

Psychiatry Case Vignettes 31 WORRY WORT A 24-year-old woman with panic disorder and generalized anxiety disorder had responded reasonably well to alprazolam (Xanax).5 mg qid. and within another week she was having daily attacks. The friend strongly suggested that she try St. prescribed by her primary care physician. and St. she began to experience an increased frequency of panic attacks (one every other day). the patient was then able to resume her usual alprazolam dosing. John’s wort). 2000 . When she reported her difficulties to her physician. Discussion This is an example of an inducer added to a substrate. he referred the patient to a psychiatrist. John’s wort (Hypericum perforatum). and he increased her standing alprazolam to 1 mg qid for 1 week. Alprazolam is a 3A4 substrate (Dresser et al. 0. Roby et al. 2000. John’s wort is a 3A4 inducer (Moore et al. Prim Psychiatry 9:28–57. she developed significant dysphoria and anhedonia. Markowitz et al. Once the amount of 3A4 available to metabolize the alprazolam had returned to baseline levels. Spence JD. In 2 weeks. These instructions effectively prevented further panic attacks and treated her pervasively anxious state. 2000). which resulted in a decrease in the blood level of alprazolam over the course of 1–2 weeks (DeVane and Nemeroff 2002. John’s wort stimulated increased production of 3A4. Her generalized anxiety was similarly heightened. The increase in active 3A4 led to increased metabolism of the alprazolam. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. and then her baseline 0.75 mg qid for 10 days. Without discussing it with her physician.5 mg qid thereafter. No other significant vegetative symptoms of depression were present. After a thorough intake. This subtherapeutic blood level of alprazolam failed to prevent the recurrence of her panic attacks. 2002 Dresser GK. 2000). then 0. References DeVane CL. She was discussing her feelings of rejection and abandonment with her best friend. she began to take the St. which the psychiatrist compensated for by increasing the dosage of the substrate (alprazolam) and discontinuing the inducer (St. the psychiatrist recommended discontinuing the St. Addition of the St. John’s wort. 2003). After breaking up with her boyfriend of 3 years. a devotee of homeopathy. Clin Pharmacokinet 38:41–57. John’s wort per the package instructions. Nemeroff CB: 2002 guide to psychotropic drug interactions.

She had responded well to nefazodone (Serzone). Goodwin B. in the past. 500 mg/day. However. titrating to a dosage of 500 mg/day as before. A further dosage increase to 600 mg/day yielded no further improvements. Donovan JL. but even after 6 weeks at that dosage there was no improvement in her depressive symptoms. Kantor E. although the psychiatrist wondered if it was that simple.000 mg/day of carbamazepine (Tegretol. Anderson GD. 2004). was started at a dosage that previously had been effective. before she developed trigeminal neuralgia. a 3A4 substrate (Bristol-Myers Squibb 2001). nefazodone. JAMA 290:1500– 1504. DeVane CL. which had risen to 14. most recent blood level. Jones SA. 11. First. Discussion This is a combined example of a substrate (nefazodone) added to an inducer (carbamazepine) and an inhibitor (nefazodone) added to a substrate (carbamazepine). primarily a 3A4 substrate (although . a competitive inhibitor of 3A4 (von Moltke et al. Clin Pharmacol Ther 67:451–457. et al: Effect of St John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. She eventually responded well to a dosage of 150 mg/day.32 Drug–Drug Interaction Primer Markowitz JS. when nefazodone. 1996. was added to carbamazepine. 2003 Moore LB. et al: St. Ucar et al. This resulted in a lower nefazodone blood level and an ineffective antidepressant trial. the presence of carbamazepine. a 3A4 inducer (Arana et al. 2000 Roby CA. Additionally. 2000 THE WORST OF BOTH WORLDS A 42-year-old woman who was taking 1. Proc Natl Acad Sci USA 97:7500–7502. et al: St. for trigeminal neuralgia experienced a recurrence of her depression. Spina et al.1 µg/mL. 1996). Second. John’s wort: effect on CYP3A4 activity. Studies have shown a greater than 10-fold decrease in nefazodone blood levels from baseline when nefazodone is coadministered with carbamazepine (Laroudie et al. He ordered a carbamazepine blood level. Her psychiatrist again prescribed nefazodone. the patient reported mildly increased fatigue and “forgetfulness” that she attributed to her depression. and her fatigue and “forgetfulness” remitted even before the nefazodone taper was completed. led to a greater amount of 3A4 than was present during the previous nefazodone trial and thus more extensive metabolism of the nefazodone during this trial. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. He tapered and discontinued the nefazodone and started the patient on venlafaxine (Effexor). 1988.1 µg/mL). 2000).

2004 Ucar M. Salazar DE. Coughtrie MW. 2004). 2000) and the emergence of mild side effects (fatigue and mild confusion). Scatina J.and 3-hydroxylated metabolites. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. Pisani F. J Pharmacol Exp Ther 276:370–379. CYP2C9 and CYP1A2. 1996. et al: Carbamazepine-nefazodone interaction in healthy subjects. 2002 . Ahern D. J Clin Psychopharmacol 20:46–53. led to antidepressant efficacy and a remission of the patient’s mild carbamazepine toxicity. Vakkalagadda GR. Leeder JS: Pathways of carbamazepine bioactivation in vitro. 1997) and whose metabolism is therefore not readily inducible by carbamazepine. Cosson JP. Because the activity of 1A2 and 2C9 was not sufficient to compensate for nefazodone’s inhibition of 3A4. 1988 Ball SE. Molloy M. Burchell B: N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. Harmatz JS. References Arana GW. 2002. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. 2004 von Moltke LL. Bristol-Myers Squibb. 2000 Pearce RE. Luurila H. J Pharmacol Exp Ther 311:1131–1137. et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. I: characterization of human cytochromes P450 responsible for the formation of 2. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. Br J Clin Pharmacol 43:619–626. there was a modest increase in the carbamazepine blood level (Laroudie et al. Drug Metab Dispos 30:1170– 1179. J Clin Psychiatry 49:448–449. PA. Clin Pharmacokinet 31:198–214. Neuvonen M. Wyeth Laboratories. the efficiency with which 3A4 was able to contribute to the metabolism of carbamazepine was impaired. NJ. Staines et al. 1997 Bristol-Myers Squibb: Serzone (package insert). 2B6. Eur J Clin Pharmacol 59:879–882. Spina et al. 2002 Spina E.Psychiatry Case Vignettes 33 1A2. Philadelphia. 1996 Staines AG. Greenblatt DJ. and effects on human hepatic CYP3A4. Epstein S. 1996 Wyeth Laboratories: Effexor (package insert). 2E1. The decision to replace the nefazodone with venlafaxine. Princeton. 2001 Laroudie C. et al: Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism. 2C8/9. comparative studies with selected SSRIs. and phase II metabolism [uridine 5′-diphosphate glucuronosyltransferase 2B7] make minor contributions to carbamazepine’s metabolism) (Pearce et al. a 2D6 substrate (Wyeth Laboratories 2002) that possesses only a mild 2D6 inhibitory profile (Ball et al.

even when titrated to a dosage of 60 mg/day. slurred speech. Over the next 5 days. After consulting with a psychiatrist colleague. References Bertschy G. et al: Probable metabolic interaction between methadone and fluvoxamine in addict patients. The increase in the blood level of methadone in this case was sufficient to generate a state of clinical opioid intoxication. having heard from various pharmaceutical representatives that this agent was specifically indicated for the treatment of OCD. even though the dosage had not been changed. Clin Pharmacol Ther 71:141–152. and hoarding behaviors. 2002 . His addiction specialist (an internist) decided to prescribe fluvoxamine (Luvox). characterized by repeated hand washing. and these symptoms remitted over the succeeding 5 days. 1994). he experienced a recurrence of his obsessive-compulsive disorder (OCD). 1996). 2002. and 2C19 inhibitor (Christensen et al. he then started the patient on citalopram (Celexa). This proved to be only partially effective in treating his OCD symptoms. Fluvoxamine is a moderately strong 3A4 inhibitor and a strong 1A2. Methadone is a 3A4 substrate (Iribarne et al. von Moltke et al. checking. 2C9. Baumann P. sedation. where he received methadone (Dolophine). The addiction specialist promptly discontinued the fluvoxamine. 1994 Christensen M. This led to an increase in the blood level of methadone.34 Drug–Drug Interaction Primer COMPULSIVE INTOXICATION A 27-year-old man with a history of opioid dependence was successfully participating in a methadone maintenance program. Mihara K. Discussion This is an example of an inhibitor added to a substrate. 80 mg/day. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). which derailed his usual ability to be socially interactive and hold down his job. Tybring G. Ther Drug Monit 16:42–45. However. 1995). The addition of the fluvoxamine significantly impaired the ability of 3A4 to efficiently metabolize the methadone. the patient progressively displayed the classic signs of opioid intoxication (miosis. Studies have found that the addition of fluvoxamine to methadone can increase methadone blood levels by 20%–100% over baseline values (Bertschy et al. and attentional deficits). Eap CB. but there was no recurrence of opioid intoxication.

Baird S. and fluvoxamine is a strong competitive inhibitor of 1A2 (Brosen 1995. et al: Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. 1996)! So in this case. Court MH. 2002). J Clin Psychopharmacol 15:125–131. but that he would steer clear of all caffeinated beverages in the future. 1995 . After a brief discussion over the phone. He reported these events to his psychiatrist. Although he had enjoyed the taste. the patient had tried a few cups of coffee. Chem Res Toxicol 9:365–373. Christensen et al. and “wired. That night. The presence of the fluvoxamine impaired the ability of 1A2 to efficiently metabolize caffeine. which proved to be both effective and well tolerated. 1996 von Moltke LL.Psychiatry Case Vignettes 35 Iribarne C. the lack of efficient 1A2 metabolism led to a much greater blood level of caffeine. one afternoon he went with some of his friends for lunch at a local coffeehouse and had two cappuccinos. When a normal amount of caffeine was ingested. Discussion This is an example of a substrate added to an inhibitor. Greenblatt DJ. which was eventually titrated to a dosage of 200 mg/day. the presence of fluvoxamine turned an innocent trip to a coffeehouse into a brush with caffeine toxicity. Caffeine is a 1A2 substrate (Miners and Birkett 1996). which also lasted much longer in the bloodstream. than would otherwise have been expected. jittery. and the clinic psychiatrist started him on fluvoxamine (Luvox). and he became quite thirsty. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. However. the patient decided that he had enjoyed such a positive response from the fluvoxamine that he did not want to change medicines. Studies have demonstrated that adding fluvoxamine will prolong the half-life of caffeine more than sixfold (Jeppesen et al. he had never become a habitual coffee drinker.” He also had to urinate every 90 minutes. 1995 WIRED A 19-year-old college student had just been diagnosed with obsessive-compulsive disorder. He visited the student mental health clinic. Clin Pharmacokinet 29(suppl):20–25. Berthou F. In years past. References Brosen K: Drug interactions and the cytochrome P450 system: the role of cytochrome P450 1A2. he could not sleep because he felt agitated.

AND ROLL A 37-year-old outpatient with schizoaffective disorder. However. Thus. His family called 911. Gen Pharmacol 27:245–249. 0. experienced a positive response to clozapine (Clozaril). 1995). Niemi et al. et al: A fluvoxamine-caffeine interaction study. Tybring G. after several previously unsuccessful medication regimens. even though the clozapine dosage had remained constant throughout (Heeringa et al. After the first 5 days. the blood level of clozapine was found to be 2. the patient complained about significant sedation. 2002. Mihara K.112 ng/mL. Birkett DJ: The use of caffeine as a metabolic probe for human drug metabolizing enzymes. excessive hand washing and hair brushing. Enzymes 3A4 and 2C19 are also significant contributors. Olesen and Linnet 2001). 600 mg/day (blood level. Discussion This is an example of an inhibitor added to a substrate. with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. Clin Pharmacol Ther 71:141–152.36 Drug–Drug Interaction Primer Christensen M. The psychiatrist thought it likely that these behaviors were a side effect of the clozapine. There. 1999. 1994. Clozapine’s metabolism occurs primarily at 1A2. perseverative ritual behaviors began to emerge (for example. He therefore decided to treat these compulsive behaviors by adding fluvoxamine (Luvox). von Moltke et al. and lithium (Eskalith). Pharmacogenetics 6:213–222. bipolar type. 1996 Miners JO. 1996 SHAKE. which he titrated to a dosage of 150 mg/day over a 10-day period. 2002 Jeppesen U. the addition of the fluvoxamine led to an impairment of clozapine’s metabolism by these P450 enzymes. several repetitive. Poulson HE. 1997. but he was loathe to discontinue one of the only medications that had been of benefit for the patient’s entrenched psychotic symptoms and impulsivity. Wetzel et al. Fluvoxamine is a strong inhibitor of 1A2. 1998). 2001. After an initial period in which the patient expe- . 2C9. 900 mg/day (blood level. 502 ng/mL). On day 11. but the psychiatrist reassured him that this was a commonly encountered side effect with fluvoxamine and that the sedation should be transient. RATTLE. Jerling et al. Loft S. resulting in a more than fourfold increase in the clozapine blood level. and flooding the toilets with toilet paper).8 mEq/L). however. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). and an ambulance transported him to the nearest emergency room. and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. the patient experienced a grand mal seizure.

Tybring G. 2001 von Moltke LL. he was readmitted after assaulting a man at a bus station who would not give him bus fare for a trip to Yucca Mountain. where his acute manic episode had been successfully treated with olanzapine (Zyprexa) monotherapy at a dosage of 20 mg/day. Engel G. and the remaining number of olanzapine tablets was exactly the same as would be expected had he been rigorously compliant . 1999 Jerling M. He was a habitual two-pack-a-day smoker. Schouten W. Lindstrom L. Court MH. Neuvonen M. Szegedi A. Ther Drug Monit 16:368–374. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. J Clin Psychopharmacol 15:125–131. 1995 Wetzel H. Anghelescu I. J Clin Psychopharmacol 18:2–9. Noncompliance with his medication was suspected. and the inpatient facility he had just left had a strict no-smoking policy. Johansson I. et al: Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Nevada. J Clin Pharmacol 41:823–832. 2002 Eiermann B. Bondesson U.Psychiatry Case Vignettes 37 rienced sedation. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Clin Pharmacol Ther 69:194–200. Clin Pharmacol Ther 71:141–152. where he intended to protest the planned deposition of nuclear waste. 2001 Olesen OV. but he had his supply of medications with him. He immediately resumed his usual level of smoking after discharge from the hospital. Beurskens R. 1998 SMOKING GUN (I) A 25-year-old man with bipolar I disorder had been recently discharged after a 4-week stay at an inpatient psychiatric facility. References Christensen M. Greenblatt DJ. et al: Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors: differential effects of fluvoxamine and paroxetine in a prospective study. Backman JT. Br J Clin Pharmacol 44:439–446. Mihara K. this toxic clozapine blood level lowered the patient’s seizure threshold enough to result in a new-onset grand mal seizure. et al: Elevated plasma levels of clozapine after concomitant use of fluvoxamine. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Pharm World Sci 21:243–244. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. 1994 Niemi M. Within 3 weeks. 1997 Heeringa M.

A trial of quetiapine (Seroquel) was tried. although it is also metabolized by 2D6 and phase II glucuronidation (Callaghan et al. so the psychiatrist again sought to stabilize him with atypical antipsychotics. References Callaghan JT. Skogh et al. Morike K. 2nd Edition. Tobacco use. 2002). he significantly increased the amount of 1A2 that was available to metabolize the olanzapine. Herraiz AG. et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. Although olanzapine blood levels are not typically obtained in standard clinical practice. but this time he remained stable for a sustained period. Ramos SI. Studies have demonstrated that smoking may increase the clearance of olanzapine by as much as 40% (Cozza et al. Clin Pharmacokinet 37:177–193. Oesterheld JR: Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s. Bergstrom RF. 1999 Carrillo JA. J Clin Psychopharmacol 23:119–127. This patient was notoriously unreliable at following up on the laboratory studies that are necessary to remain on most conventional mood stabilizers. 2003 Cozza KL. 2003 Schrenk D. At the time. Dahl ML. Brockmeier D. is a significant 1A2 inducer (Schrenk et al. P-Glycoproteins. and the patient again improved and was discharged. 1998. 2002 . 1998 Skogh E. the psychiatrist attributed this sequence of events to idiosyncratic differences in medication response in a given patient. Armstrong SC. Reis M. Discussion This is an example of an inducer added to a substrate. et al: Therapeutic drug monitoring data on olanzapine and its N-demethyl metabolite in the naturalistic clinical setting. Ptak LR. Eur J Clin Pharmacol 53:361–367. it seems clear that the increases in olanzapine’s metabolism and the subsequent decreases in the blood levels of olanzapine caused by smoking tobacco can produce significant clinical decompensations. DC. 2003. Washington. et al: Olanzapine: pharmacokinetic and pharmacodynamic profile. American Psychiatric Publishing. It was not until after he attended a P450 grand rounds presentation that he revised this assessment. The use of tobacco should be one of the issues that are closely followed when prescribing olanzapine (and clozapine). 1999). 2003). When the patient resumed smoking. resulting in a decrease in the blood level of olanzapine (Carrillo et al. et al: Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. via cigarette smoking. Ther Drug Monit 24:518–526. Zevin and Benowitz 1999). UGTs.38 Drug–Drug Interaction Primer with his regimen. Olanzapine is a 1A2 substrate.

1999. 1997. Stevens and Wrighton 1993). and he consumed two large cups of tea each day. However. and he increased his intake of caffeine in order to “perk up” so he could do his best. Discussion This is an example of an inhibitor added to a substrate. 300 mg/day (blood level. and his symptoms abated. the auxiliary pathways for clozapine’s metabolism mitigate the ability of caffeine to significantly raise clozapine levels. depressive type. He reported these symptoms to his psychiatrist. 2000. Caffeine is both a substrate and a reasonably potent competitive inhibitor of 1A2 (Hartter et al.Psychiatry Case Vignettes 39 Zevin S. Benowitz NL: Drug interactions with tobacco smoking: an update. 10 mg/day. Raaska et al.145 ng/mL. Specifically. fluoxetine (Prozac). Fluoxetine (in concert with its active metabolite. Clin Pharmacokinet 36:425–438. This proved to be good advice. he was taking one 200-mg caffeine tablet each morning. as the lack of work responsibilities led the patient to curtail his caffeine intake. only modest increases in clozapine levels are generally observed with this combination (Hagg et al. The long-standing coadministration of clozapine and fluoxetine may partially explain why a relatively low dosage of clozapine (300 mg/day) generated a somewhat higher than expected. who checked a clozapine blood level and advised the patient to take a few days off from his new job. 40 mg/day.” On the contrary. and diazepam (Valium). However. and significant associated anxiety had done reasonably well for the past year on clozapine (Clozaril). Enzymes 3A4 and 2C19 are also significant contributors. Thus. the presence of the fluoxetine likely changed the “P450 landscape” in ways that made caffeine an effective competitive inhibitor. 2004). but therapeutic. he experienced increased sedation. ataxia. and 2C19 (Greenblatt et al. Olesen and Linnet 2001). 2003. A follow-up clozapine blood level was 622 ng/mL (Odom-White and deLeon 1996). However. norfluoxetine) is a strong inhibitor of 2D6 and a moderate inhibitor of 3A4. 2C9. When the patient reported to his psychiatrist that he was feeling better. and blurry vision. after 5 days he did not feel “perky. Miners and Birkett 1996). Clozapine’s metabolism occurs primarily at 1A2. He recently started a volunteer job at the local Veterans Affairs hospital. with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. despite the primary role of 1A2. The clozapine blood level was found to be 1. he took a more careful history and discovered the patient’s change in caffeine intake. 1999 CAFFEINE COMPLICATIONS A 32-year-old man with schizoaffective disorder. clozapine blood level . 589 ng/mL).

Basic Clin Pharmacol Toxicol 94:13–18. This led to a significant increase in the clozapine blood level. 1997 Greenblatt DJ. Br J Clin Pharmacol 56:679–682. With the removal of the competitive inhibitor. Br J Clin Pharmacol 49:59–63. J Clin Pharmacol 41:823–832. Thus. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. References Eiermann B. Engel G. et al: Human cytochromes and some newer antidepressants: kinetics. even though there had been no increase in the dosage. Spigset O. caffeine. metabolism. fluoxetine’s inhibition of all of the major non-1A2 P450 enzymes involved in clozapine’s metabolism rendered clozapine’s metabolism even more primarily dependent on the activity and availability of 1A2 than usual. et al: Effects of caffeine intake on the pharmacokinetics of melatonin. 2000 Hartter S. a probe drug for CYP1A2 activity. Mjorndal T. Johansson I. 1996 Odom-White A. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. 2003 Miners JO. 2001 Raaska K. Nordmark A.40 Drug–Drug Interaction Primer (589 ng/mL). 1996 Olesen OV. Harmatz JS. J Clin Psychopharmacol 19(suppl):23S–35S. 1993 . and his symptoms remitted. Gen Pharmacol 27:245–249. it was able to compete with substrate-binding sites on 1A2 to a sufficient degree to act as a functionally significant competitive inhibitor of 1A2’s ability to metabolize the clozapine. et al: Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. von Moltke LL. These factors explain why the addition of a generally stimulating substance (caffeine) led to paradoxical sedation and anergy. J Pharmacol Exp Ther 266:964–971. (See “Enuresis (I)” later in the chapter for a more complete discussion of the interaction of clozapine and fluoxetine. 2004 Stevens JC. Laitila J. Raitasuo V. Birkett DJ: The use of caffeine as a metabolic probe for human drug metabolizing enzymes. et al: Effect of caffeine-containing versus decaffeinated coffee on serum clozapine concentrations in hospitalised patients. when an avidly bound 1A2 substrate like caffeine was added to the regimen. 1999 Hagg S. deLeon J: Clozapine levels and caffeine. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. Rose DM. and blurry vision. and drug interactions. Br J Clin Pharmacol 44:439–446.) However. which caused the patient to experience increased sedation. ataxia. the patient’s clozapine blood level returned to baseline. J Clin Psychiatry 57:175–176.

Clearly. even though the olanzapine dosage had not been changed. he opted to discontinue the fluvoxamine and instead initiated a trial of citalopram (Celexa). However. contrary to the psychiatrist’s concerns. because he now was taking both divalproex sodium and olanzapine. Fluvoxamine is a strong inhibitor of 1A2. claiming to be too “wiped out” to participate in groups or walks. and he experienced a remission of his OCD symptoms without a manic relapse (for the time being). olanzapine (Zyprexa). However. although it is also metabolized by 2D6 and phase II glucuronidation (Callaghan et al. The patient slept 13 hours a day.” resulting in an increase in the blood level of olanzapine and oversedation. although use of this medication was kept to a minimum because of the concern about inducing a manic episode. Studies in which fluvoxamine was added to olanzapine have demonstrated a more than doubling of olanzapine blood levels as a result (Weigmann et al. was added. Olanzapine is a 1A2 substrate. 2001). 2002. . 87 µg/mL). and he stayed in his bed for most of the time that he was awake. 2D6 and phase II glucuronidation were not able to handle the increased metabolic “burden. Prior to his hospitalization. 2001. After consulting the hospital pharmacist. he had been maintained on divalproex sodium (Depakote). the psychiatrist did not consider this an optimal therapeutic response.250 mg/day (blood level.Psychiatry Case Vignettes 41 BEDSTUCK A 25-year-old man with comorbid bipolar I disorder and obsessive-compulsive disorder (OCD) was hospitalized because of a manic episode. 2C9. 20 mg/day. Niemi et al. His OCD had responded to fluvoxamine (Luvox) in the past. 1. Thus. The patient’s sedation then remitted. the psychiatrist carefully added fluvoxamine and titrated it to a dosage of 100 mg/day. Although his sedation acutely overwhelmed his OCD symptoms. he then experienced a recurrence of his OCD symptoms (severe contamination obsessions with cleaning compulsions). von Moltke et al. This sedation was especially surprising because the inpatient treatment team was anticipating a possible antidepressant-induced manic switch. the patient was not activated but rather became quite sedated. 1995). Soon after the admission. Watching closely for a manic relapse. and his mania remitted over the next 10 days. Within 5 days. and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. his psychiatrist felt that the benefits of treating the OCD symptoms with fluvoxamine outweighed the risks. 1999). the addition of fluvoxamine impaired the ability of 1A2 to significantly contribute to the metabolism of the olanzapine. Discussion This is an example of an inhibitor added to a substrate.

10 days later. which eventually produced a remission of psychosis and no side effects. titrated to a dosage of 1. Ther Drug Monit 23:410–413.000 mg/day (blood level. so he and his psychiatrist agreed on a trial of carbamazepine (Tegretol). . Tybring G. He had not tolerated previous trials of lithium and divalproex sodium (Depakote) because of tremors on lithium and hair loss on divalproex (not prevented by vitamins with zinc and selenium). However. Greenblatt DJ. Clin Pharmacol Ther 71:141–152. Clin Pharmacol Ther 69:194–200. he was again grandiose and paranoid. He had been compliant with this medication. Bergstrom RF. et al: Fluvoxamine but not sertraline inhibits the metabolism of olanzapine: evidence from a therapeutic drug monitoring service. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Backman JT. Clin Pharmacokinet 37:177–193. 2002 Niemi M. Ptak LR. he consented to rehospitalization to formulate an appropriate defense strategy from a safe location. Olanzapine is a 1A2 substrate.000 mg/day of carbamazepine. Gerek S.6 µg/mL). Zeisig A.42 Drug–Drug Interaction Primer References Callaghan JT. although it is also metabolized by 2D6 and phase II glucuronidation at the 1A4 enzyme (Callaghan et al. Neuvonen M. 1995 Weigmann H. believing that his professors were “in cahoots with the Masons” to secretly control the leadership of all the G7 nations and that only he could foil this plot. but during finals week at his college he became acutely manic and required psychiatric hospitalization. et al: Olanzapine: pharmacokinetic and pharmacodynamic profile. He was then discharged from the hospital. 1999 Christensen M. After consulting with the hospital pharmacist. 2001 von Moltke LL. 9. Mihara K. 2001 CONSPIRACY THEORY A 21-year-old man with bipolar I disorder was being maintained on olanzapine (Zyprexa). J Clin Psychopharmacol 15:125–131. He experienced improvement in his manic symptoms by day 7 while taking 1. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. After sharing his concerns with his psychiatrist. the psychiatrist titrated the olanzapine dosage to 40 mg/day. Court MH. Discussion This is an example of an inducer added to a substrate. 1999. 20 mg/day.

This decrease in the olanzapine blood level led to the reemergence of paranoid and grandiose delusions. 1998 Rambeck B. Ucar et al. Neuvonen M. On the basis of this information. et al: Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test. Carbamazepine is an inducer of 3A4. et al: Metabolism and excretion of mood stabilizers and new anticonvulsants. Molloy M. 1996 Skogh E. Reis M. Ther Drug Monit 24:512–517. 1999 Linnet K: Glucuronidation of olanzapine by cDNA-expressed human UDP-glucuronosyltransferases and human liver microsomes. 2004). Br J Clin Pharmacol 45:176– 178. Epstein S. Ther Drug Monit 21:171–174. Olesen OV: Free and glucuronidated olanzapine serum concentrations in psychiatric patients: influence of carbamazepine comedication. 1996. and glucuronidation enzyme 1A4 (Arana et al. Clin Pharmacokinet 31:309–324. Parker et al. thus compensating for carbamazepine’s inductive effects. Preston T. Ptak LR. Ketter et al. Dahl ML. 2002 Spina E. Rambeck et al. 1996 Ucar M. Wolf P: Pharmacokinetic interactions of the new antiepileptic drugs. over the course of 2–3 weeks. Eur J Clin Pharmacol 59:879– 882. Clin Pharmacokinet 37:177–193. 1A2. 1988 Bottiger Y. 1988. 1999. Stahle L: Lamotrigine drug interactions in a TDM material. 1996. 2002). 2002 Linnet K. Pisani F. et al: Olanzapine: pharmacokinetic and pharmacodynamic profile. causing a corresponding decline in the olanzapine blood level (Skogh et al. et al: Therapeutic drug monitoring data on olanzapine and its N-demethyl metabolite in the naturalistic clinical setting. 1999. Ther Drug Monit 24:518–526. References Arana GW. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. Studies in which carbamazepine was added to olanzapine have found significant (roughly 40%) decreases in olanzapine blood levels (Linnet and Olesen 2002). Cora-Locatelli G. Thus. the hospital pharmacist advised the psychiatrist to double the olanzapine dosage to 40 mg/day. Pritchard P. Svensson JO. Specht U. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. 1998. Clin Pharmacokinet 31:198–214. with the result that the olanzapine was more quickly and efficiently metabolized. Hum Psychopharmacol 17:233– 238. Luurila H. 2004 . Bergstrom RF.Psychiatry Case Vignettes 43 Linnet 2002). et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. Cell Mol Neurobiol 19:511–532. Spina et al. Bottiger et al. Frye MA. the addition of carbamazepine led to an increase in the amounts of all these enzymes. J Clin Psychiatry 49:448–449. 1999 Ketter TA. 2002 Parker AC. 1999 Callaghan JT.

thus necessitating the admission. Because of the patient’s volatility and lability. His psychiatrist therefore decided to initiate a clozapine trial. which yielded a clozapine blood level of 453 ng/mL. the psychiatrist ordered another set of blood levels for clozapine and carbamazepine. In the first week after this carbamazepine dosage had been reached. and 3A4. 115 µg/ mL). Enzymes 3A4 and 2C19 are also significant contributors.000 mg/day over the course of 2 weeks (blood level. He had already failed trials with every atypical antipsychotic except for clozapine (Clozaril). Clozapine is also metabolized in part by the phase II glucuronidation enzyme 1A4 (Breyer-Pfaff and Wachsmuth 2001). The patient was less frankly delusional. It . 2C9. and the current divalproex. and to use sedative agents for short-term behavioral control. The patient was admitted in a flagrantly paranoid state. Carbamazepine is an inducer of multiple P450 enzymes. He titrated the drug up to a dosage of 500 mg/day. Clozapine’s metabolism occurs primarily at 1A2. gabapentin (Neurontin). He titrated the dosage of carbamazepine up to 1. rather than try to raise the clozapine dosage. Previous “mood stabilizers” that had been tried included lithium. although he still displayed remarkably poor frustration tolerance. 2B6. However. 160 mg/day.500 mg/day (blood level. was hospitalized following a failed trial of ziprasidone (Geodon). 1. While the carbamazepine blood level had not changed appreciably. which the patient had never previously tried. Discussion This is an example of an inducer added to a substrate. thus requiring locked-door seclusion on several occasions. the clozapine blood level was now 211 ng/mL. The psychiatrist consulted the hospital pharmacist. Olesen and Linnet 2001).7 µg/mL). bipolar type. who strongly advised him to discontinue the carbamazepine. 1 week later. he would very quickly revert back to a paranoid stance and become acutely threatening toward staff and peers alike. 1997. and he denied further concerns about his neighbors. Before embarking on any major course of action. the patient displayed less agitation and more of an ability to cope with small frustrations. He had become acutely threatening to neighbors whom he believed were persecuting him. and divalproex sodium (Depakote). his psychiatrist decided to begin a trial of carbamazepine (Tegretol). with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. 8. and he accordingly became more threatening again. specifically including 1A2. the patient’s paranoia rapidly grew more intense. When frustrated.44 Drug–Drug Interaction Primer PLAYING WITH FIRE A 32-year-old man with schizoaffective disorder.

the clinician should have a compelling reason that would justify exposing the patient to such risks. Rambeck et al.Psychiatry Case Vignettes 45 also induces the glucuronidation enzyme 1A4 (Arana et al. Svensson JO. Jerling et al. These various enzymes were therefore able to more efficiently metabolize the clozapine (DeVane and Nemeroff 2002. 1997 Faucette SR. The discontinuation of the carbamazepine would be expected to yield a return to the baseline clozapine blood level in 2–3 weeks. Stahle L: Lamotrigine drug interactions in a TDM material. Drug Metab Dispos 32:348–358. with clozapine causing a roughly 1% incidence of agranulocytosis and carbamazepine potentially causing aplastic anemia and other blood dyscrasias. References Arana GW. 1994). This drop in the clozapine blood level caused the patient to experience a resurgence of his paranoid delusions and threatening behavior. Br J Clin Pharmacol 44:439–446. Ther Drug Monit 21:171–174. Wachsmuth H: Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Parker et al. with the result that the clozapine blood level dropped by about 50% (typical for this scenario) even though the dosage of clozapine had not been decreased. Thus the addition of the carbamazepine led to an increased production of 1A2. Ucar et al. Drug Metab Dispos 29:1343– 1348. et al: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. 1999 Breyer-Pfaff U. Lindstrom L. Nemeroff CB: 2002 guide to psychotropic drug interactions. Molloy M. Miners and Birkett 1998. Both of these agents are capable of significant bone marrow suppression. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. Ther Drug Monit 16:368–374. 1996. Bondesson U. The marrow suppression of these agents is certainly additive. 2002 Eiermann B. 1988 Bottiger Y. It was this set of concerns that led the pharmacist to advise discontinuation of the carbamazepine. 2004. Apart from this complex pharmacokinetic interaction. 1998. Bottiger et al. Faucette et al. 2004). Spina et al. Hamilton GA. 3A4. Prim Psychiatry 9:28–57. Wang H. 1996. Engel G. and the phase II glucuronidation enzyme 1A4. 2004 Jerling M. adverse hematological event. et al: Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. and possibly synergistic. Because this medication combination carries with it an increased risk of causing a severe. 1994 . 2001 DeVane CL. Johansson I. J Clin Psychiatry 49:448– 449. there is a potential pharmacodynamic interaction of great importance and concern. 1999. Epstein S. 1988.

Br J Clin Pharmacol 45:176– 178. Niemi et al. 2001. Birkett DJ: Cytochrome P4502C9: an enzyme of major importance in human drug metabolism.” Discussion This is an example of reversal of inhibition. full manic symptoms rapidly emerged following the discontinuation of the fluvoxamine. Fluvoxamine is a strong inhibitor of 1A2. The psychiatrist felt compelled to both increase the olanzapine to 20 mg/day and add divalproex sodium (Depakote). Preston T. dysphoria. et al: Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test. 2C9. and this successfully restored a state of euthymia. J Clin Pharmacol 41:823–832. 2004 THE LAW OF UNINTENDED CONSEQUENCES (I) A 31-year-old man was initially treated with 200 mg/day of fluvoxamine (Luvox) for his presenting complaints of obsessional thinking. Pisani F. Clin Pharmacokinet 31:309–324. When his bipolar diathesis (in the form of emerging manic symptoms) became more evident later in the treatment. 1998 Rambeck B. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Luurila H. although it is also metabolized by 2D6 and phase II glucuronidation (Callaghan et al. and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. 6 months later. which he titrated to a dosage of 1. Olanzapine is a 1A2 substrate. and associated depressive symptoms. 1996 Ucar M. Clin Pharmacokinet 31:198–214. the presence of the fluvoxamine impaired the ability of 1A2 to significantly contribute to the metabolism of the olanzapine. Br J Clin Pharmacol 45:525–538. 2001 Parker AC. but he complained about oversedation and feeling “blunted. 1995). However. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. Wolf P: Pharmacokinetic interactions of the new antiepileptic drugs. The patient’s manic symptoms were eventually stabilized. 118 µg/mL). was added. Neuvonen M. 1999).46 Drug–Drug Interaction Primer Miners JO. 10 mg/day. yielding a higher blood . olanzapine (Zyprexa). von Moltke et al. Rather than increase the dosage of olanzapine or add another mood stabilizer. Contrary to expectations. 1996 Spina E. the psychiatrist and patient agreed that the best course would be to discontinue the fluvoxamine. however. Thus. Pritchard P. Eur J Clin Pharmacol 59:879– 882. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. 1998 Olesen OV.500 mg/day (blood level. he again began to experience an emergence of hypomanic symptoms. 2002. Specht U.

Therefore. even though the olanzapine dosage had not been decreased. her psychiatrist decided to prescribe fluoxetine (Prozac). et al: Fluvoxamine but not sertraline inhibits the metabolism of olanzapine: evidence from a therapeutic drug monitoring service. 2002 Niemi M. Zeisig A. 2001 von Moltke LL. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. She typically experienced a seasonal variation in her mood. Clin Pharmacol Ther 71:141–152. 516 ng/mL). Ptak LR. Gerek S. which the psychiatrist addressed by both increasing the olanzapine dosage and adding divalproex. 2001). 600 mg qhs (blood level. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Court MH. with the discontinuation of fluvoxamine. After meeting with the patient and discussing treatment options. and had the olanzapine dosage been increased to 20 mg/day with the discontinuation of the fluvoxamine. Backman JT. had maintained clinical stability with clozapine (Clozaril).Psychiatry Case Vignettes 47 level of olanzapine than would have been expected had fluvoxamine not been present. Neuvonen M. depressive type. Mihara K. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. 1995 Weigmann H. Bergstrom RF. with especially prominent anergia. Tybring G. Clin Pharmacokinet 37:177–193. Clin Pharmacol Ther 69:194–200. This occult decrease in the olanzapine blood level unexpectedly precipitated the development of full manic symptoms. divalproex might not have been a necessary addition to the regimen or a lower divalproex dosage and blood level might have produced antimanic efficacy without sedation and anergy. Studies in which fluvoxamine was added to olanzapine have demonstrated a more than doubling of olanzapine blood levels as a result (Weigmann et al. leading to a decrease (probably by about 50%) in the blood level of olanzapine. 2001 ENURESIS (I) A 38-year-old woman with schizoaffective disorder. Ther Drug Monit 23:410–413. and one winter she became more depressed than usual. J Clin Psychopharmacol 15:125–131. 1999 Christensen M. 1A2 was able to resume its baseline (higher) level of metabolic activity. References Callaghan JT. Greenblatt DJ. Had this interaction been anticipated. et al: Olanzapine: pharmacokinetic and pharmacodynamic profile. .

In this case. 1997 Greenblatt DJ. et al: Effect of fluoxetine on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenia. J Clin Pharmacol 41:823–832. 2C9. 2C9. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. the patient’s depressive symptoms were improved. et al: Human cytochromes and some newer antidepressants: kinetics.079 ng/mL. The addition of fluoxetine thus impaired the ability of 3A4. Facciola G. 1997. Olesen and Linnet 2001). and drug interactions. After 4 weeks. He instructed the patient to skip her next dose and then resume the clozapine at a dosage of 300 mg qhs. References Eiermann B. her oversedation and accompanying enuresis remitted. Harmatz JS. leading to progressive enuresis. Stevens and Wrighton 1993). despite sleeping at least 12 hours each night. J Pharmacol Exp Ther 266:964–971. Even though the functioning of 1A2 was basically spared by fluoxetine. this was apparently not sufficient to offset the inhibition of the other enzymes and prevent an increase in the clozapine blood level. Enzymes 3A4 and 2C19 are also significant contributors. and 2C19 (Greenblatt et al. Her sedation became so profound that she was no longer able to reliably wake up when her bladder was full. Br J Clin Pharmacol 44:439–446. which had increased to 1. 1993 . 1999. Johansson I. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. the increase in the clozapine blood level led to increased sedation and enuresis. Discussion This is an example of an inhibitor added to a substrate. Fluoxetine (in concert with its active metabolite. Engel G. Avenoso A. He ordered a clozapine blood level. metabolism. 2C19. 2001 Spina E. Clozapine’s metabolism occurs primarily at 1A2. J Clin Psychopharmacol 19(suppl):23S–35S. Studies have found that adding fluoxetine to clozapine is likely to increase clozapine blood levels by just over 50% (Spina et al.48 Drug–Drug Interaction Primer 20 mg/day. and her next clozapine blood level was 581 ng/mL. she reported this embarrassing symptom to her psychiatrist. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. 1999 Olesen OV. 1998). Int Clin Psychopharmacol 13:141–145. Within 1 week. After several episodes of enuresis. and 2D6 to make significant contributions to the overall metabolism of clozapine. von Moltke LL. norfluoxetine) is a strong 2D6 inhibitor and a moderate inhibitor of 3A4. 1998 Stevens JC. but she felt even more lethargic and anergic than before.

Ann Pharmacother 28:191–195. 1995). 1998) and fluvoxamine is a strong inhibitor of 1A2. Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. Mamiya et al. and he accepted their advice. the patient felt progressively more sedated and slightly unsteady. 2002.” assuming that these were transient side effects of his new medicine that would soon abate. Thus. 1994. 14.” as well as a full array of neurovegetative depressive symptoms. 1994 .7 µg/mL (Mamiya et al. 1 week after reaching 150 mg/day. During this fluvoxamine dosage titration. Niemi et al. 2C9. the patient lost his balance and fell down a flight of stairs in his home. References Cadle RM. Rodriguez-Barradas MC. His obsessional ruminations about his “lost glories. but he did not want to be a “complainer. One summer. However. 2001). Zenon GJ 3rd.Psychiatry Case Vignettes 49 HOW THE MIGHTY HAVE FALLEN A 56-year-old teacher with a seizure disorder had been virtually seizure free for the past 10 years while taking phenytoin (Dilantin). He was immediately taken to the local emergency room. Now he was being rejected by a place he had considered a kind of home.” and he decided to just “stick it out. the addition of the fluvoxamine impaired the ability of 2C9 and 2C19 to significantly contribute to the metabolism of phenytoin.5 µg/mL). he received the news that he would not be rehired by the school for the coming academic year. he ruminated about how he had attended the same school as a teenager. where his phenytoin blood level was found to be 46. During the intake. with the plan to titrate to a dosage of 150 mg/day and then wait a few weeks for a possible response. von Moltke et al. and he basically lay there until a friend happened to drop by 6 hours later. This event. along with the recent death of his spouse from pancreatic cancer. and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. His friends advised him to visit a psychiatrist. Discussion This is an example of an inhibitor added to a substrate. 2001. led the psychiatrist to start the patient on fluvoxamine (Luvox). He was too delirious and debilitated to summon help himself. and in his day he had been the class president and the starting quarterback. The patient’s state of phenytoin toxicity culminated in his delirium and subsequent fall. et al: Fluconazole-induced symptomatic phenytoin toxicity. led him into his first severe depressive episode. 300 mg/day (blood level. and this caused a more than threefold increase in the phenytoin blood level.

resulting in a hospital admission. 20 mg/day. Ther Drug Monit 23:75–77. Mihara K.1 µg/mL).50 Drug–Drug Interaction Primer Christensen M. The patient did well after the setback until it was time for the fellow to relocate and a new child and adolescent psychiatry fellow assumed treatment of the patient. Epilepsia 39:1317–1323. Yukawa E. The neurologist appreciated the input. and the eventual diagnosis of a seizure disorder (which his mother had). Clin Pharmacol Ther 71:141–152. Shimamoto J. he readily agreed and helped orchestrate a crossover titration from fluoxetine to mirtazapine (Remeron). Clin Pharmacol Ther 69:194–200. When he was taken to the emergency room. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). et al: The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. 2002 Mamiya K. and he asked if the fellow would consider switching him to another antidepressant. He then had his first seizure. but 1 month later the patient had another seizure. Ieiri I. 1998 Mamiya K. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. and in collaboration with the fellow. a full neurological workup. 2001 Niemi M. Kojima K. Court MH. 1995 TRANSITIONS A 17-year-old with major depressive disorder was responding well to fluoxetine (Prozac). the patient mentioned that he had long noticed that the fluoxetine impaired his ability to ejaculate. Greenblatt DJ. et al: Phenytoin intoxication induced by fluvoxamine. 14. Tybring G. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. J Clin Psychopharmacol 15:125–131. Backman JT. he carefully titrated the dosage of phenytoin to 160 mg/day (blood level. This meant that dosing of the phenytoin should be slower than normal and that blood levels should be checked at a lower dosage than would be typical. 2001 von Moltke LL. Two months into that treatment. His neurologist planned to prescribe phenytoin (Dilantin). Neuvonen M. This crossover proceeded uneventfully. Because the new fellow was not as conversant with P450 issues as his predecessor.6 µg/mL. . but the child and adolescent psychiatry fellow who was treating the patient for his depression took the initiative to contact the neurologist and share his understanding that the fluoxetine would impair the metabolism of phenytoin. his phenytoin blood level was found to be only 6.

The first psychiatry fellow recognized that the addition of phenytoin to fluoxetine would follow the “substrate added to inhibitor” paradigm. Preskorn SH: Drug-drug interaction in reverse: possible loss of phenytoin efficacy as a result of fluoxetine discontinuation. and 3A4 (Greenblatt et al. Rodriguez-Barradas MC. metabolism. Ann Pharmacother 28:191–195. Mamiya et al. with the result that the phenytoin level then fell below the therapeutic range and the patient experienced another seizure (Shad and Preskorn 1999).Psychiatry Case Vignettes 51 Discussion This is an example of reversal of inhibition. Epilepsia 39:1317–1323. 1994. Shimamoto J. Ieiri I. any amount of phenytoin that was to be added would be expected to generate a higher blood level than would have been achieved had the fluoxetine not been present (Shader et al. J Clin Psychopharmacol 14:375–376. J Clin Psychopharmacol 19:471–472. fluoxetine. Greenblatt DJ. the maintenance of this therapeutic blood level at this dosage of phenytoin was dependent on the continued presence of the 2C9/2C19 inhibitor. 1999 Shader RI. Because 2C9 and 2C19 were significantly inhibited. References Cadle RM. their ability to efficiently metabolize phenytoin was impaired. et al: Human cytochromes and some newer antidepressants: kinetics. Once the final phenytoin dosage of 160 mg/day was generating a stable therapeutic blood level. von Moltke LL. 1999 Mamiya K. Stevens and Wrighton 1993). et al: Fluconazole-induced symptomatic phenytoin toxicity. Therefore. Harmatz JS. 1994 Stevens JC. von Moltke LL: Fluoxetine inhibition of phenytoin metabolism. and drug interactions. 1999. 1998 Shad MU. 1993 . Fluoxetine (in concert with its active metabolite. J Clin Psychopharmacol 19(suppl):23S–35S. Discontinuation of the fluoxetine by the new child and adolescent psychiatry fellow in the course of the crossover to mirtazapine allowed 2C9 and 2C19 to resume their baseline uninhibited levels of activity. 1994 Greenblatt DJ. Please see “Nystagmus” in Chapter 6 for a detailed discussion of the plasma protein–binding dimension of the fluoxetine-phenytoin interaction. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. 2C19. et al: The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. 1998). 1994). norfluoxetine) is a strong inhibitor of 2D6 and a moderate inhibitor of 2C9. J Pharmacol Exp Ther 266:964–971. Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. Zenon GJ 3rd.

It has also been shown to not increase levels of alprazolam (Xanax.” The psychiatrist agreed to start him on disulfiram. my belief is that. and after the patient was acutely stabilized. metabolized by 3A4) (Diquet et al. disulfiram’s presumed strong 2C19 inhibition significantly impaired the ability of this enzyme to contribute to the metabolism of phenytoin. 1998). Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. 2000). Kiorboe 1966). He reported to the psychiatrist that he had found disulfiram (Antabuse) to be a helpful way to motivate him to stay “dry. . resulting in an increase in the phenytoin blood level and the accompanying delirium. and it has been shown to increase phenytoin blood levels. and there was no evidence of a disulfiram–alcohol reaction. 1996). it may be that 2C9 inhibition could also have played a role. the patient seemed intoxicated and irritable. Discussion This is an example of an inhibitor added to a substrate.52 Drug–Drug Interaction Primer DRY DELIRIUM A 48-year-old man with alcohol dependence had just been admitted to the medical floor of a hospital for the treatment of active delirium tremens. which led the hospital staff to believe that he had somehow procured alcohol while on one of his brief trips to the emergency room entrance to smoke a cigarette. Mamiya et al. Thus. the hospitalist placed him on phenytoin (Dilantin). In view of this evidence. 1990. Disulfiram is certainly a strong 2E1 inhibitor. The patient had already had a seizure in the emergency room. and a lorazepam (Ativan) taper to address the delirium tremens. However. 400 mg/day (blood level. A Breathalyzer borrowed from the emergency room confirmed that he was still “dry. see “Clots” in Chapter 4). Dresser et al. 1994.9 µg/mL. 1999. 1999. Because disulfiram’s inhibitory profile is otherwise not well characterized.2 µg/mL). at the very least. and perhaps not even a likely one. 500 mg/day. disulfiram acts as an inhibitor of 2C19 as well as of 2E1. but this is merely a possibility that cannot be excluded as yet.” A stat phenytoin blood level was then ordered and found to be 31. Kharasch et al. Five days later. Disulfiram also has no known inhibitory profile with regard to phase II glucuronidation or P-glycoprotein systems. in a manner similar to ticlopidine (Ticlid. he had been compliant with the disulfiram. Disulfiram has been shown to also increase blood levels of diazepam (Valium. Ono et al. 16. A psychiatric consultant visited the patient. but beyond that its enzymatic activities have not been well characterized (Emery et al. 1978. metabolized primarily by 2C19 and secondarily by 3A4) (MacLeod et al. who seemed willing to make a serious attempt to curtail his drinking.

1998 Ono S. Shimamoto J. Jubert C. Epilepsia 7:246–249. 1996 ALCOHOL-FREE INTOXICATION A 35-year-old woman with a history of alcohol dependence and panic disorder had been taking disulfiram (Antabuse). Rodriguez-Barradas MC.Psychiatry Case Vignettes 53 References Cadle RM. Hankins DC. et al: Fluconazole-induced symptomatic phenytoin toxicity. 2C19. Hatanaka T. 5 mg tid. et al: Duration of cytochrome P-450 2E1 (CYP2E1) inhibition and estimation of functional CYP2E1 enzyme half-life after single-dose disulfiram administration in humans. 100 mg/day. et al: Interaction of disulfiram with benzodiazepines. et al: Lack of single-dose disulfiram effects on cytochrome P-450 2C9. However. that he was also starting (initial dosage. 1966 MacLeod SM. Lamiable D. in the past. Drug Metab Dispos 27:717–723. and her psychiatrist agreed to prescribe this until the sertraline (Zoloft). et al: Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6. and 3A4 activities: evidence for specificity toward P-450 2E1. 1990 Dresser GK. et al: Lack of interaction between disulfiram and alprazolam in alcoholic patients. Jubert C. J Pharmacol Exp Ther 291:213–219. after 4 days the patient reported that she had had no more panic attacks but also that she felt much more sedated and almost “drunk. for the past 2 years. Eur J Clin Pharmacol 38:157–160. 1999 Kharasch ED. various stressors in her life had led to a resurgence of debilitating panic attacks. Thummel KE. Sellers EM. Her panic attacks had responded to diazepam (Valium). et al: The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. Clin Pharmacokinet 38:41–57. and this helped her to remain abstinent from alcohol for this period. Giles HG. Zenon GJ 3rd. However. The psychiatrist instructed the patient to use a pill cutter to halve the . which caused a remission of the oversedation but some return of panic attacks. 25 mg/ day) began to provide some relief. 2D6. Xenobiotica 26:1155–1166. Ann Pharmacother 28:191–195. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Epilepsia 39:1317–1323. Gujadhur L. 2000 Emery MG. Miyazawa S. 1994 Diquet B. Ieiri I. Spence JD. 250 mg/day. although not nearly as badly as before the diazepam was initiated.” as compared with her prior response to this dosage of diazepam. 1978 Mamiya K. The psychiatrist decreased the diazepam dosage to 2 mg tid. 2C19 and the 3A subfamily. 1999 Kiorboe E: Phenytoin intoxication during treatment with Antabuse (disulfiram). Clin Pharmacol Ther 24:583–589.

Epilepsia 7:246–249. Hatanaka T. Disulfiram is certainly a strong 2E1 inhibitor. Dresser et al. Lamiable D. Jubert C. 1999 Kharasch ED. Jubert C. Eur J Clin Pharmacol 38:157–160. on the basis of clinical effect. Thummel KE. 2000). Gujadhur L. my belief is that. Discussion This is an example of a substrate added to an inhibitor. 2C19 and the 3A subfamily. Disulfiram also has no known inhibitory profile with regard to phase II glucuronidation or P-glycoprotein systems. 1990. This is the likely mechanism by which disulfiram elevates the blood level of diazepam. Ono et al. metabolized primarily by 2C19 and secondarily by 3A4) (MacLeod et al. Diazepam is a substrate primarily of 2C19 and secondarily of 3A4 (Ono et al. to a 40% reduction of the diazepam dosage. Miyazawa S. Xenobiotica 26:1155–1166. 1990 Dresser GK. J Pharmacol Exp Ther 291:213–219. 1978 Ono S. 2D6. 1978. 1996). and 3A4 activities: evidence for specificity toward P-450 2E1. References Diquet B. 2000 Emery MG. 1966 MacLeod SM. Clin Pharmacol Ther 24:583–589. Drug Metab Dispos 27:717–723.54 Drug–Drug Interaction Primer diazepam 2-mg tablets and then to take 3 mg tid. it has been shown to not increase levels of alprazolam (Xanax. 2C19. Spence JD. Also. 1999. Giles HG. disulfiram acts as an inhibitor of 2C19 as well as of 2E1. This explains why the patient became oversedated while taking a dosage of diazepam that she had previously tolerated. et al: Lack of interaction between disulfiram and alprazolam in alcoholic patients. Sellers EM. et al: Duration of cytochrome P-450 2E1 (CYP2E1) inhibition and estimation of functional CYP2E1 enzyme half-life after single-dose disulfiram administration in humans. and it has been shown to increase phenytoin blood levels. but beyond that its enzymatic activities have not been well characterized (Emery et al. et al: Lack of single-dose disulfiram effects on cytochrome P-450 2C9. In view of this evidence. 1999. The psychiatrist compensated for this effect by carefully titrating. 1996). 1999 Kiorboe E: Phenytoin intoxication during treatment with Antabuse (disulfiram). metabolized by 3A4) (Diquet et al. Hankins DC. Clin Pharmacokinet 38:41–57. at the very least. Kiorboe 1966). Disulfiram has also been shown to increase blood levels of diazepam (Valium. which provided optimal relief from panic without oversedation. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. et al: Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6. Kharasch et al. et al: Interaction of disulfiram with benzodiazepines. 1996 .

“Since I’m going to eat whatever I want after I leave the hospital. personal communication. sweaty. May 2002). Wang JS. but another shortterm option would be to decrease the dosage of glipizide. 2001 Wen X. which was found to be 51 mg/dL (S. and at that dosage he maintained consistent blood glucose readings between 120 and 170 mg/dL. why restrict my intake now?” The psychiatrist agreed to liberalize his diet as long as he ate more than just the desserts on his and his peers’ trays. he did refuse to abide by a diabetic diet. he refused all psychiatric medications. Curry TB. he reported feeling severely light-headed. Pharmacogenetics 11:803– 808. The nurses checked the glucose level by fingerstick. but he readily took his prescribed glipizide (Glucotrol). His glipizide was then titrated to 5 mg/day.5 mg/day. Kivisto KT. and nervous.Psychiatry Case Vignettes 55 JUST DESSERTS A 74-year-old man with bipolar I disorder and type II diabetes mellitus was hospitalized due to a manic episode. Discussion This is an example of an inhibitor added to a substrate. Consequently. the patient agreed to a trial of divalproex sodium (Depakote). Armstrong. et al: In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9). 2001). an increase in the glipizide blood level led to a decrease in the patient’s blood glucose. After 5 days of taking the divalproex. and divalproex is a 2C9 inhibitor (Wen et al. Because glipizide is an oral hypoglycemic agent. et al: Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. He was slightly tachycardic (110 beats per minute) but not at all orthostatic. which had been his practice to date. with accompanying clinical signs of hypoglycemia. Gallagher S. Glipizide is a 2C9 substrate (Kidd et al. Br J Clin Pharmacol 52:547–553. The addition of the divalproex led to a significant impairment in the ability of 2C9 to efficiently metabolize the glipizide. even though the glipizide dosage had not been further increased at that time. This would probably be best addressed by switching to another hypoglycemic agent whose metabolism would not be affected by divalproex. References Kidd RS. among having many other metabolic roles. During the initial phase of his inpatient stay. However. the blood level of glipizide rose. however.C. stating. titrated to a dosage of 500 mg/day. After these and other maneuvers fostered the emergence of a therapeutic alliance. 2001 . 2. 2001).

For his part. Because 3A4 was not able to entirely compensate for this 2C19 inhibition. Thus. She was more efficient and unflustered during a tax season than she could ever recall. One March. References Caraco Y. She shared this information with her psychiatrist. Predictably. she always became more nervous around March because of the crush of yearly tax submissions. Wood AJ: Interethnic difference in omeprazole’s inhibition of diazepam metabolism. This increase in the diazepam blood level might have ordinarily produced unwanted sedation or cognitive slowing. she experienced increasing indigestion and heartburn pain. she experienced an unusual absence of inner turmoil during what was usually a stressful period. he had been surprised that he had not received any extra phone calls from the patient for the past month. Diazepam is a substrate primarily of 2C19 and secondarily of 3A4 (Ono et al. such that the increase seems to have produced an as yet unrecognized clinical benefit for this patient. for this problem. 1995 . Nousbaum et al. and her use of diazepam had remained stable over the years. the addition of the omeprazole significantly impaired the ability of 2C19 to contribute to the metabolism of diazepam. 5 mg tid. He prescribed omeprazole (Prilosec). Tateishi T. and omeprazole is a strong inhibitor of 2C19 as well as an inducer of 1A2 (Furuta et al. 2001. Her psychiatrist would supply her with one or two as-needed doses of diazepam per week to offset this period of heightened stress. Discussion This is an example of an inhibitor added to a substrate. 1995). 1994). and her coworkers supported this perception. Clin Pharmacol Ther 58:62–72.56 Drug–Drug Interaction Primer THE ANXIOUS ACCOUNTANT (I) A 55-year-old CPA with generalized anxiety disorder had responded well for 20 years to treatment with diazepam (Valium). 1996). Within 5 days. which prompted a visit to her internist. but it appears that this patient had been chronically and mildly undertreated. 20 mg/day. She continued to enjoy a sense of calm that persisted beyond the tax season. there was an increase in the blood level of diazepam. who was puzzled but pleasantly so. but he ascribed that to character development and the patient’s finding more mature coping mechanisms with age. She did not require any extra doses of diazepam for the entire tax season. Studies have demonstrated that the addition of omeprazole to diazepam will typically increase blood levels of diazepam by roughly 40% (Caraco et al.

Psychiatry Case Vignettes 57 Furuta S. with the discontinuation of the omeprazole and replacement with a proton pump inhibitor (pantoprazole) that lacks a 2C19 inhibitory profile. which was likely slightly suboptimal. the initial addition of the omeprazole significantly impaired the ability of 2C19 to contribute to the metabolism of diazepam. 1994). The psychiatrist eventually recognized the subtle benefit that the presence of the omeprazole had conferred. et al: Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6. Berthou F. she experienced what felt like her old anxieties and worries. The lack of any such stressors prompted the psychiatrist to ask more questions. Within a few days. Xenobiotica 31:1–10. and omeprazole is a strong inhibitor of 2C19 as well as an inducer of 1A2 (Furuta et al. but no acute stressors were present. 2C19 was able to return to its greater baseline level of activity. Xenobiotica 26:1155–1166. Within another 5 days. which actually proved helpful for this patient (Caraco et al. Hatanaka T. the psychiatrist did some quick research and then decided to increase her standing dosage of diazepam to 7 mg tid. there was an increase in the blood level of diazepam. cimetidine and omeprazole. Am J Gastroenterol 89:371–375. 2001 Nousbaum JB. et al: Inhibition of drug metabolism in human liver microsomes by nizatidine. 1996 THE ANXIOUS ACCOUNTANT (II) The patient in the previous case continued to do well for several months. This led to more efficient metabolism of the diazepam and subsequent decline of the diazepam blood level back to its previous level. Discussion This is an example of reversal of inhibition (with a happy ending). diazepam is a substrate primarily of 2C19 and secondarily of 3A4 (Ono et al. until the omeprazole was taken off her insurance company’s formulary. However. 1996). Nousbaum et al. et al: Four-week treatment with omeprazole increases the metabolism of caffeine. 1994 Ono S. Kamada E. As mentioned in the previous case (“The Anxious Accountant [I]”). Carlhant D. specifically about medication changes. Her internist replaced this with pantoprazole (Protonix). 2C19 and the 3A subfamily. 1995). and he successfully reproduced this by increasing the dosage of diazepam by 40% (from 5 mg tid to 7 mg tid). Thus. 2001. Miyazawa S. When she revealed the recent change from omeprazole to pantoprazole. she felt like her new old self again. . Suzuki T. Because 3A4 was not able to entirely compensate for this 2C19 inhibition.

initially at 50 mg/day. 2001 Nousbaum JB. and it was eventually titrated to a dosage of 250 mg/day. Hatanaka T. to which the patient’s manic symptoms appeared to respond (K. Xenobiotica 31:1–10. 1995 Furuta S. 1994 Ono S. Miyazawa S. Clin Pharmacol Ther 58:62–72. Walters. Berthou F. and phenytoin (Dilantin). First. 1 mg bid. she did not want the olanzapine dosage further increased. phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. Tateishi T. clonazepam (Klonopin). Discussion This is an example of an inhibitor (topiramate) added to a substrate (phenytoin) and (probably) a substrate (topiramate) added to an inducer (phenytoin). the patient reported ataxia and drowsiness.7 µg/mL. She was already unhappy about taking the olanzapine. the . and topiramate is an inhibitor of 2C19 (Anderson 1998) and an inducer of 3A4 (Benedetti 2000). Wood AJ: Interethnic difference in omeprazole’s inhibition of diazepam metabolism. The psychiatrist decreased the phenytoin dosage to 300 mg/day. L. Am J Gastroenterol 89:371–375. Because the activity of 2C9 was not able to fully compensate. 400 mg/day (most recent blood level. Thus the addition of topiramate significantly impaired the ability of 2C19 to contribute to the metabolism of phenytoin. 10 mg qhs. Her psychiatrist decided to add topiramate (Topamax).2 µg/mL). Lin.58 Drug–Drug Interaction Primer References Caraco Y. with the plan to further titrate the dosage as clinically indicated. and she rejected lithium and divalproex sodium (Depakote) out of hand as potential mood stabilizers. having gained 8 pounds since she started that medication 1 year ago. 2C19 and the 3A subfamily. Kamada E. August 2002). Carlhant D. Suzuki T. and the phenytoin blood level then returned to its pre-topiramate value. 1998). et al: Inhibition of drug metabolism in human liver microsomes by nizatidine. Topiramate was retained in the regimen. Therefore. 1994. Xenobiotica 26:1155–1166. After 3 days. Mamiya et al. 1996 SENSITIVE A 40-year-old woman with a seizure disorder and bipolar I disorder was being maintained on the following regimen: olanzapine (Zyprexa). et al: Four-week treatment with omeprazole increases the metabolism of caffeine. cimetidine and omeprazole. A new phenytoin level was drawn. 12. personal communication. she then required hospitalization for a manic episode. which was 17. However. et al: Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6.

Zenon GJ 3rd. 2C19. 2002). Ann Pharmacother 32:554–563. Raucy 2003). 1999. 1994 Chetty M. 1998 Benedetti MS: Enzyme induction and inhibition by new antiepileptic drugs: a review of human studies. the presence of the phenytoin likely necessitated a higher dosage (probably roughly double) of topiramate to produce a clinical response than would have been needed in the absence of phenytoin. 2003. Ann Pharmacother 28:191–195. Sachdeo et al. Guerrini R. Ther Drug Monit 25:700–708. and uridine 5′diphosphate glucuronosyltransferase (UGT) 1A4 (Bottiger et al. Ther Drug Monit 20:60– 62. 2003 . This may be attributable to a relatively rapid change in the blood level. Chetty et al. Therefore. It may seem odd that the patient reported symptoms consistent with phenytoin toxicity even though her highest phenytoin blood level still fell well within the therapeutic range. age. 2002)—in this case. Phenytoin is an inducer of multiple enzymes. Second.Psychiatry Case Vignettes 59 inhibition of 2C19 by topiramate resulted in an increase in the blood level of phenytoin (Sachdeo et al. et al: Fluconazole-induced symptomatic phenytoin toxicity. 1996. Seymour MA: Phenytoin autoinduction. Miller R. Fundam Clin Pharmacol 14:301–319. 2000 Bottiger Y. The psychiatrist was able to partially compensate for this increase in the phenytoin blood level by decreasing the dosage from 400 mg/day to 300 mg/day. References Anderson GD: A mechanistic approach to antiepileptic drug interactions. Gibson et al. 3A4. although a significant portion of this compound is renally excreted (roughly 70%) and not hepatically metabolized at all (Ortho-McNeil Pharmaceutical 2000). it stands to reason that topiramate is likely a substrate within the 1A family of phase II glucuronidation substrates. by nearly 50%. 2002. Gatti G. Rodriguez-Barradas MC. Studies have demonstrated that the addition of phenytoin will generally decrease the blood level of topiramate by 50% (Ferrari et al. specifically including 2C9. but it is more likely that this individual was simply idiosyncratically sensitive to phenytoin side effects at the upper portion of the therapeutic range. Rambeck et al. 1999 Cadle RM. 1998 Ferrari AR. 1998. et al: Influence of dosage. and co-medication on plasma topiramate concentrations in children and adults with severe epilepsy and preliminary observations on correlations with clinical response. Stahle L: Lamotrigine drug interactions in a TDM material. Svensson JO. Because there is no current evidence that the P-glycoprotein transporter plays a role here. topiramate is a substrate of phase II glucuronidation (not well understood beyond that at present). Ther Drug Monit 21:171–174.

she experienced the new onset of obsessions around order and compulsive checking. 2001. 5 mg bid. who made the diagnosis of obsessivecompulsive disorder (OCD).60 Drug–Drug Interaction Primer Gibson GG. Ieiri I. Clin Pharmacokinet 31:309–324. These symptoms prompted her to visit a psychiatrist. 2000 Rambeck B. 2003 Sachdeo RC. with a smaller contribution from 3A4 (Ono et al. Levy RH. This increase in the diazepam blood level caused the patient to .” With the beginnings of her first serious intimate relationship. Niemi et al. Raritan. 1994). 2002 SLEEPING BEAUTY A 21-year-old woman was receiving diazepam (Valium). Discussion This is an example of an inhibitor added to a substrate. el-Sankary W. 1995). 1998 Ortho-McNeil Pharmaceutical: Topamax (package insert). et al: The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. 2C9. the addition of the fluvoxamine significantly impaired the ability of 2C19 and 3A4 to efficiently metabolize the diazepam. Shimamoto J. 1996 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Toxicology 181–182:199–202. von Moltke et al. Thus. Fluvoxamine is a strong inhibitor of 1A2. Although she was able to drive safely. Sachdeo SK. Epilepsia 39:1317–1323. He started the patient on fluvoxamine (Luvox). 2002 Mamiya K. she felt that her ability to concentrate in her college classes was diminished. who then decreased the dosage of diazepam to 2 mg bid. leading to an increase in the blood level of diazepam (Perucca et al. from her family physician for a complaint of “free-floating anxiety. Epilepsia 43:691–696. OrthoMcNeil Pharmaceutical. Specht U. After 1 week at this dosage. et al: Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients. She reported these difficulties to her psychiatrist. NJ. 2002. 50 mg bid initially and titrated to an eventual dosage of 200 mg/day. and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. Wolf P: Pharmacokinetic interactions of the new antiepileptic drugs. the patient reported that she was sleeping more than 11 hours each night and that she was still sleepy during the day. Diazepam is primarily a substrate of 2C19. 1996). Drug Metab Dispos 31:533–539. Her sedation remitted and her OCD symptoms continued to improve over the succeeding weeks. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene.

Ten days later.75 mEq/L). He had been seizure free for the previous 2 years. 300 mg/day (blood level. so his psychiatrist discontinued the fluvoxamine. Clin Pharmacol Ther 71:141–152. 12. the patient tolerated this lower dose of diazepam without difficulty. The psychiatrist nicely compensated for fluvoxamine’s inhibition of diazepam’s metabolism by decreasing the dose of diazepam from 5 mg bid to 2 mg bid. 1995 ANTIDEPRESSANT WITHDRAWAL SEIZURE A 22-year-old man with bipolar I disorder and a seizure disorder was being maintained on lithium. The phenytoin was the most recent addition to this regimen.Psychiatry Case Vignettes 61 become sedated. Clin Pharmacol Ther 69:194–200. Greenblatt DJ.7 µg/mL. Miyazawa S. Mihara K.4 µg/mL). Clin Pharmacol Ther 56:471–476. et al: Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6. because he had been taking a different anticonvulsant before he was switched to phenytoin. increasing libido. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. in part. Cipolla G. The patient began to display emerging manic symptoms (decreasing need for sleep. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. 2002 Niemi M. Neuvonen M. Hatanaka T. fluvoxamine (Luvox). 0. Tybring G. References Christensen M. Xenobiotica 26:1155–1166. 900 mg/day (blood level. Her positive response was possibly due. Backman JT. increased rate of speech and distractibility). 2001 Ono S. J Clin Psychopharmacol 15:125–131. et al: Inhibition of diazepam metabolism by fluvoxamine: a pharmacokinetic study in normal volunteers. to some anxiolytic contribution (albeit not through direct γ-aminobutyric acid agonism) from the fluvoxamine. Gatti G. 1996 Perucca E. 2C19 and the 3A subfamily. Court MH. . 150 mg/day. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). and phenytoin (Dilantin). the patient experienced a seizure and his phenytoin blood level was found to be only 4. 1994 von Moltke LL. Although the blood level of diazepam while the patient was taking 4 mg/day along with the fluvoxamine might not have been quite as high as the blood level was at 10 mg/day without fluvoxamine.

et al: The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. 1998 Mamiya K. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. et al: Fluconazole-induced symptomatic phenytoin toxicity. Mamiya et al. Shimamoto J. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Neuvonen M. J Clin Psychopharmacol 15:125–131. resulting in more efficient metabolism of the phenytoin and a subsequent decrease in the phenytoin blood level to the subtherapeutic range. which led to a psychotic decompensation with manic features and subsequent hospitalization. Tybring G. had been noncompliant with his olanzapine (Zyprexa). 1994. bipolar type. the therapeutic blood level of phenytoin at a dosage of 300 mg/day relied on the inhibition of phenytoin’s metabolism at 2C9 and 2C19 by fluvoxamine (Mamiya et al. 1995 LESS IS MORE A 32-year-old man with schizoaffective disorder. Niemi et al. References Cadle RM. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. and fluvoxamine is a strong inhibitor of 1A2. and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. Rodriguez-Barradas MC. 2001 Niemi M. Clin Pharmacol Ther 71:141–152. Epilepsia 39:1317–1323. This problem was eventually addressed by the psychiatrist’s increasing the phenytoin dosage to 600 mg/day. which produced a blood level of 10. Ther Drug Monit 23:75–77. von Moltke et al. 1995). 2002 Mamiya K. Zenon GJ 3rd. 2001. 2C9. Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. 1994 Christensen M. et al: Phenytoin intoxication induced by fluvoxamine. Yukawa E. Ann Pharmacother 28:191–195. 2C9 and 2C19 resumed their higher baseline levels of activity. Court MH. 2002.62 Drug–Drug Interaction Primer Discussion This is an example of reversal of inhibition. 2001). This caused the patient to have his first seizure in 2 years. 1998). 2001 von Moltke LL. His inpatient psychiatrist decided that he should begin receiving a deca- . Kojima K. Greenblatt DJ. Backman JT.8 µg/mL. Mihara K. Thus. 20 mg qhs. Ieiri I. When the fluvoxamine was discontinued. Clin Pharmacol Ther 69:194–200.

1A2. One week later.100 cells/µL.Psychiatry Case Vignettes 63 noate preparation of haloperidol (Haldol) to address his recurrent medication noncompliance. 2004). and possibly pertinent glucuronidation enzymes that were produced by carbamazepine’s induction died off. 2C9. 2004. the patient’s psychotic symptoms had almost completely remitted. 2B6. he instead chose to decrease the haloperidol back to 10 mg/day. and 3A4. 1996. 1988. It also induces uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 (Arana et al. Miners and Birkett 1998. he began to experience cogwheel rigidity and mild akathisia. the patient was slightly calmer. One week later. 9. In preparation for this. Faucette et al. Also. 1999. 2003). 2D6. Rambeck et al. The haloperidol was further increased to 20 mg/day in an effort to treat these psychotic symptoms. with the patient taking the same dosage of haloperidol. Ten days later. 1A2. This led to a decrease in the metabolism of haloperidol and a subsequent increase in the haloperidol blood level. but the psychiatrist discovered that the patient’s white blood count had dropped from 6. the psychotic symptoms began to diminish. 1998.7 µg/mL). Kudo and Ishizaki 1999). and metabolically available levels of 3A4. the resulting blood level was now sufficient to generate both an antipsychotic response . Haloperidol is metabolized by 3A4. Lucas et al. the patient’s psychotic symptoms continued to improve. and glucuronidation enzymes returned to their (lower) pre-carbamazepine baselines. Ucar et al. 1999. Discussion This is an example of reversal of induction. After 2 weeks at this dosage of carbamazepine. titrating to a dosage of 800 mg/day (blood level. but his paranoid delusions and auditory hallucinations persisted with unabated strength. The carbamazepine increased the amounts of 3A4. 1A2. The psychiatrist added benztropine (Cogentin) for the cogwheeling and strongly considered adding propranolol (Inderal) for the akathisia. and possibly pertinent phase II glucuronidation enzymes that were available to metabolize the haloperidol. the psychiatrist added carbamazepine (Tegretol). he was started on oral haloperidol. Spina et al. and carbamazepine is an inducer of multiple P450 enzymes. including the akathisia. Bottiger et al. and phase II glucuronidation (Desai et al. leading to a haloperidol blood level that was potentially subtherapeutic despite the use of fairly high doses (Hesslinger et al. the “extra” 3A4. 10 mg/day. 1998. specifically including 1A2. because his current presentation was characterized by more violence than usual. The carbamazepine was abruptly discontinued. At about the same time.100 cells/µL to 2. 1A2. Parker et al. however. 2001. 1996. but after a conversation with the hospital pharmacist. as had all of his side effects. When the carbamazepine was discontinued. In this case. Yasui-Furukori et al.

Br J Clin Pharmacol 45:176– 178. Pisani F. 2004 Hesslinger B. J Clin Psychiatry 49:448–449. Molloy M. Luurila H. Stahle L: Lamotrigine drug interactions in a TDM material. Mihara K. Drug Metab Dispos 32:348–358. 2003 SYMMETRY An 11-year-old boy was diagnosed with comorbid major depressive disorder and obsessive-compulsive disorder (OCD). Eur J Clin Pharmacol 54:639–643. J Clin Psychopharmacol 19:310–315. 1996 Spina E. 1998 Parker AC. 2004 Yasui-Furukori N. CNS Drugs 15:469–494. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Hamilton GA. Normann C. Langosch JM. Gilfillan DJ. 1999 Kudo S. Pritchard P. 1998 Miners JO. Ther Drug Monit 21:171–174. et al: Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients. 1999 Desai HD. 1999 Lucas RA. 2001 Faucette SR. allowed for the remission of these side effects with a continuation of the therapeutic response. Epstein S. Jann MW: Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. Wolf P: Pharmacokinetic interactions of the new antiepileptic drugs. Specht U. A decrease in the haloperidol dosage from 20 mg/day to 10 mg/day. Clin Pharmacokinet 31:309–324. et al: Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test. Kondo T. J Clin Psychopharmacol 23:435–440. Bergstrom RF: A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism. et al: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Neuvonen M. Clin Pharmacokinet 31:198–214. Br J Clin Pharmacol 45:525–538. His intrusive thoughts and ritu- . 1988 Bottiger Y. 1996 Ucar M. Seabolt J. Preston T. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. Clin Pharmacokinet 37:435–56. 1998 Rambeck B. Ishizaki T: Pharmacokinetics of haloperidol: an update. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. Svensson JO. Wang H. Eur J Clin Pharmacol 59:879– 882. along with a little benztropine. et al: Significant dose effect of carbamazepine on reduction of steady-state plasma concentration of haloperidol in schizophrenic patients. References Arana GW. Birkett DJ: Cytochrome P4502C9: an enzyme of major importance in human drug metabolism.64 Drug–Drug Interaction Primer and parkinsonism and akathisia.

without the need for further dosage changes of either venlafaxine or clomipramine (C. initially at a dosage of 25 mg qhs. The fluvoxamine dosage was decreased to 100 mg/day. Even though the clomipramine + desmethylclomipramine total was within the desired range. He therefore decided to discontinue the fluvoxamine and started the patient on venlafaxine (Effexor). total. but he developed tinnitus while taking this medication. with a remission of the apathy but also a loss of efficacy against the OCD symptoms. The patient was initially tried on fluoxetine (Prozac). 103 ng/mL. resulting in blood levels of clomipramine + desmethylclomipramine that were significantly greater than they would have been had fluvoxamine not been present (Spina et al. The fluoxetine was discontinued. with remission of both depressive and OCD symptoms. Discussion This is an example of a substrate added to an inhibitor. Thus.5 mg/day. Curiously. desmethylclomipramine. 24 ng/mL. but the patient developed a severe apathy syndrome at this dosage.Psychiatry Case Vignettes 65 als around preserving symmetry in his surroundings had significantly derailed his schoolwork and his ability to maintain normal peer relationships. August 2002). The 2D6 enzyme performs subsequent hydroxylation. with 1A2 serving as a secondary enzyme (Nielsen et al. von Moltke et al. 130 ng/mL (optimal range for this lab was 70–200 ng/mL). 1A2. yielding the following levels: clomipramine. desmethylclomipramine. When the fluvoxa- . with mild to moderate OCD symptom reduction. 127 ng/mL. Lachner. the clinician was concerned (erroneously) about the high clomipramine level leading to cardiac toxicity. several P450 enzymes (3A4. 1995). The dosage of this medication was initially titrated up to 150 mg/day. and 2C19) were impaired in their ability to efficiently metabolize clomipramine. 3A4. 1993). After 10 days. total. 171 ng/mL (range was 220–500 ng/mL). The psychiatrist decided to add clomipramine (Anafranil). 52 ng/mL. the patient began to enjoy a positive clinical response. 1996). desmethylclomipramine. 41 ng/mL (range was 150–300 ng/mL). 20 mg/day. the patient’s blood levels were as follows: clomipramine. 2002. 352 ng/mL. personal communication. 404 ng/mL. Desmethylclomipramine is clomipramine’s primary metabolite via demethylation by 2C19 and 3A4. The clomipramine dosage was then increased to 50 mg qhs. Fluvoxamine is a strong inhibitor of 1A2 and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. total. and he was then started on fluvoxamine (Luvox). and 2D6. After the venlafaxine dosage was titrated to 112. Clomipramine is a tertiary-amine tricyclic antidepressant whose metabolism depends most on the intact functioning of 2C19. when clomipramine was added in the presence of fluvoxamine. blood levels were as follows: clomipramine.

et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. 1993 von Moltke LL. Br J Clin Pharmacol 43:619–626. especially insomnia. 40 mg qhs. which is only a mild 2D6 inhibitor (Ball et al. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). 1995 VIGILANCE ALWAYS A 35-year-old woman was being treated in an intensive outpatient setting for a significant worsening of her depressive symptoms. 900 mg/day. CYP2C9 and CYP1A2. and sertraline (Zoloft). Tybring G. and effects on human hepatic CYP3A4. comparative studies with selected SSRIs. 600 mg/day. Clin Pharmacol Ther 71:141–152. Myers CW: Clomipramine: a tricyclic antidepressant effective in obsessive compulsive disorder. et al: Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism. J Clin Psychopharmacol 15:125–131. Ther Drug Monit 15:243–246. Mihara K. 1996 Spina E. Flinois JP. For the clomipramine + fluvoxamine (50 mg/day) regimen. Pollicino AM. 1990 Nielsen KK. 1997 Christensen M. these ratios may be important considerations as we refine our ability to reliably target pharmacological interventions to specific illness profiles.66 Drug–Drug Interaction Primer mine was replaced by venlafaxine. Scatina J. For the clomipramine + venlafaxine regimen. et al: Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects. amitriptyline (Elavil). Her medications included nefazodone (Serzone). References Ball SE. Greenblatt DJ. This represents a roughly 28-fold ratio difference between these regimens! Because clomipramine is a potent serotonergic reuptake inhibitor. Beaune P. and desmethylclomipramine is primarily a noradrenergic uptake inhibitor (Kelly and Myers 1990). which . DICP 24:739–744. 1997). J Pharmacol Exp Ther 277:1659–1664. Court MH. Avenoso A. This case suggests that at least some persons with OCD may respond more favorably to a “mixed action” antidepressant with both serotonergic and noradrenergic components rather than one focusing just on serotonin. It is worth noting the vastly different ratios of clomipramine to desmethylclomipramine found in this case. lithium. 2002 Kelly MW. the total level decreased more than threefold. the ratio was roughly 7:1. Ahern D. et al: The biotransformation of clomipramine in vitro: identification of the cytochrome P450s responsible for the separate metabolic pathways. the ratio was roughly 1:4.

with 1A2 serving as a secondary enzyme (Venkatakrishnan et al. the amitriptyline level was 472 ng/mL. Both because of her insomnia and as a prudent measure. von Moltke LL. Discussion This is an example of an inhibitor added to a substrate. 1998). with lorazepam (Ativan) at night as needed for sleep. The 2D6 enzyme performs subsequent hydroxylation. References Alderman J. The extremely low nortriptyline blood level indicates that strong 3A4 inhibition prevented much of the conversion (demethylation) of amitriptyline to nortriptyline by 3A4. the patient remained asymptomatic. 1997 Solai LK. et al: Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. 1996). 3A4. He promptly discontinued the amitriptyline and started the patient on mirtazapine (Remeron) for insomnia and antidepressant augmentation. Fortunately. However. Amitriptyline is a tertiary-amine tricyclic antidepressant whose metabolism depends most on the intact functioning of 2C19. Nefazodone is a strong 3A4 inhibitor (von Moltke et al. thus leading to what was almost certainly an increase in the amitriptyline level (to 472 ng/mL). et al: Effect of sertraline on plasma nortriptyline levels in depressed elderly. 1998 . Khushalani.Psychiatry Case Vignettes 67 had been increased from 100 mg/day to 150 mg/day in the previous few days. this is a very high blood level for a comparatively low dosage of amitriptyline. These antidepressants (nefazodone and sertraline) markedly impaired the ability of 3A4 and 2D6 to metabolize the amitriptyline. 2D6 inhibition likely added to the direct elevation of the amitriptyline level by cutting off one of amitriptyline’s accessory metabolic pathways (hydroxylation). 1997). Solai et al. The nefazodone had been added to the amitriptyline roughly 6 months earlier (S. Greenblatt DJ. even though the dosage had not been changed. Greenblatt DJ. the psychiatrist checked her amitriptyline + nortriptyline blood level. 1997 Venkatakrishnan K. personal communication. 1997. J Clin Psychopharmacol 17:284–291. J Clin Pharmacol 38:112–121. July 2002). Preskorn SH. and at 150 mg/day. and the nortriptyline level was less than 20 ng/mL. Certainly. To his surprise. et al: Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4. J Clin Psychiatry 58:440–443. Mulsant BH. sertraline is a moderate 2D6 inhibitor (Alderman et al. Nortriptyline is amitriptyline’s primary metabolite via demethylation by 2C19 and 3A4. and her amitriptyline was discontinued before she had any adverse consequences of her frankly toxic blood level. Pollock BG. and 2D6.

The patient carefully followed his instructions. that was produced and therefore available to metabolize the haloperidol. the psychiatrist 1) advised the patient to immediately discontinue the phenobarbital. and he reported his difficulties to his psychiatrist. “Be careful! We’re watching you!”—led to increasing paranoia. He had recently started a volunteer job. Kudo and Ishizaki 1999). Over the several weeks during which this increased production of 3A4 (and possibly pertinent glucuronidation enzymes) occurred. The nephew had a seizure disorder and had been treated with phenobarbital. at which point he would taper the haloperidol back to 10 mg/day. J Pharmacol Exp Ther 276:370–379. and possibly pertinent glucuronidation enzymes. 1996 DO YOU HEAR WHAT I HEAR? A 32-year-old man with chronic paranoid schizophrenia had done reasonably well on haloperidol (Haldol). After taking a careful interval history. However.68 Drug–Drug Interaction Primer von Moltke LL. Phenobarbital is an inducer of 3A4 (among other P450 enzymes) (Rautlin de la Roy et al. Discussion This is an example of an inducer added to a substrate. 1971) and phase II glucuronidation (Hachad et al. 2D6. and phase II glucuronidation (Desai et al. and 3) instructed him to increase his haloperidol to 20 mg/day and to report when extrapyramidal symptoms begin to emerge. his psychotic symptoms remitted over the next 3 weeks. but he then experienced a gradual increase in his previous auditory hallucinations over the next several weeks. He lived with his sister and nephew. et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. 10 mg/day. The phenobarbital did ameliorate his onset insomnia. Haloperidol is metabolized by 3A4. 2 mg/day. 2002). and the accompanying stress led to some new-onset insomnia. The . 1980). The increasingly frequent and intense barrage of voices—telling him. albeit at the price of some transient stiffness and cogwheel rigidity. 1A2. there was still nearly a 1-month supply of unused phenobarbital in the house. 2) supplied the patient with lorazepam (Ativan) as-needed for insomnia. with benztropine (Cogentin). The patient decided to take two tablets each night (each tablet was 30 mg) to help him get to sleep. Greenblatt DJ. The addition of phenobarbital led to an increase in the amount of 3A4. 2001. Harmatz JS. but this had been recently switched to valproate. and a hospitalization was avoided. there was a decrease in the blood level of haloperidol and a resulting recurrence of psychotic symptoms (Linnoila et al.

August 2002). the patient gradually improved in terms of her psychotic and depressive symptoms. after which fluoxetine (Prozac). Viukari M. 0. resulting in the emergence of extrapyramidal symptoms. This problem persisted even when the dosage of risperidone was decreased to 0.25 mg/day. Ragueneau-Majlessi I. The psychiatrist opted to substitute citalopram (Celexa). Clin Pharmacokinet 37:435–456. for the fluoxetine. However. Fluoxetine (in concert with its active metabolite. and after 3 weeks her galactorrhea remitted.” there was an increase in the haloperidol blood level to a level greater than the patient’s baseline. Seabolt J. norfluoxetine) is a strong . 20 mg/day. Am J Psychiatry 137:819–821. 1980 Rautlin de la Roy Y DE. Over the next 3 weeks. et al: Effect of anticonvulsants on plasma haloperidol and thioridazine levels. These symptoms served as a sign that the haloperidol could then be tapered back to its baseline dosage. 1971 GALACTIC INCONVENIENCE A 15-year-old with a psychotic depression first received risperidone (Risperdal). References Desai HD. 20 mg/day. personal communication. Discussion This is an example of an inhibitor added to a substrate. she began to display galactorrhea.25 mg every other day. Ther Drug Monit 24:91–103. Curiously. 2001 Hachad H. Levy RH: New antiepileptic drugs: review on drug interactions. Ishizaki T: Pharmacokinetics of haloperidol: an update. Jann MW: Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. Vaisanen K. was added. The lorazepam was supplied both to address the insomnia complaint and to prevent any possible sedative-hypnotic withdrawal state that might have occurred with the discontinuation of the phenobarbital. as the “extra” 3A4 (and possibly glucuronidation enzymes) that had been induced by phenobarbital “died off. CNS Drugs 15:469–494. Risperidone is a substrate of 2D6 and 3A4 (DeVane and Nemeroff 2001). at no time did she display any movement abnormalities (S. Presse Med 79:350. 1999 Linnoila M.Psychiatry Case Vignettes 69 psychiatrist then recommended a temporary increase in the haloperidol dosage to compensate for these inductive effects. After the phenobarbital was discontinued. et al: Reduction of the blood level of rifampicin by phenobarbital (in French). 2002 Kudo S. for 1 week with no ill effects. Beauchant G. Breuil K. Ruths. 1 month after the fluoxetine was started.

about a 75% increase in the blood level of the risperidone active moiety (Spina et al. Nemeroff CB: An evaluation of risperidone drug interactions. Stevens and Wrighton 1993). J Pharmacol Exp Ther 266:964– 971. Avenoso A. J Clin Psychopharmacol 22:419–423. et al: Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction. 2001 Forest Pharmaceuticals: Celexa (package insert). leading to galactorrhea. 1999. 4 mg/day. there was an increase in serum prolactin. Because the increased blood level of risperidone resulted in more blockade of D2 receptors. and drug interactions. J Clin Psychopharmacol 19(suppl):23S–35S. and citalopram. 2004 Greenblatt DJ. the reversal of 3A4 inhibition and significant decrease in 2D6 inhibition led to a return of the risperidone blood level to baseline. the addition of the fluoxetine significantly impaired the ability of 3A4 and 2D6 to efficiently metabolize the risperidone. 1993 SEDATED AKATHISIA A 25-year-old man with schizoaffective disorder and a history of polysubstance abuse was being maintained on risperidone (Risperdal). Forest Pharmaceuticals 2004). et al: Human cytochromes and some newer antidepressants: kinetics. Scordo MG. 2001 DeVane CL. The absence of extrapyramidal symptoms was peculiar but likely indicates that her tuberoinfundibular dopamine pathway was more sensitive to increased D2 blockade than was her nigrostriatal dopamine pathway. Forest Pharmaceuticals. 1999 Spina E. This led to an increase in the blood level of risperidone. MO. and . was substituted. J Clin Psychopharmacol 21:408–416. When fluoxetine was discontinued. Eur Neuropsychopharmacol 11:275–283. 2002). and because dopamine functions as “prolactin inhibitory hormone” in the tuberoinfundibular dopamine pathway. References Brosen K. Studies in which fluoxetine was added to risperidone have revealed.70 Drug–Drug Interaction Primer 2D6 inhibitor and a moderate 3A4 inhibitor (Greenblatt et al. Thus. Harmatz JS. St. 2002 Stevens JC. on average. This led to a remission of her galactorrhea. metabolism. Louis. even though the dosage of risperidone had not been increased. Naranjo CA: Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. von Moltke LL. which is only a mild to moderate inhibitor of 2D6 (Brosen and Naranjo 2001.

and buspirone is a 3A4 substrate (Kivisto et al. then soon awaken and resume his pacing. J Clin Psychopharmacol 21:408–416. about a 75% increase in the blood level of the risperidone active moiety (Spina et al. The discontinuation of the fluoxetine led to a reversal of the 3A4 and 2D6 inhibition. Thus the addition of the fluoxetine significantly impaired the ability of 3A4 to metabolize the buspirone and the ability of both 3A4 and 2D6 to metabolize the risperidone. even though their dosages had not been changed. Studies in which fluoxetine was added to risperidone have revealed. Although the psychiatrist did not understand what had occurred. sit. 20 mg/day. He had received the regimen of quetiapine (Seroquel) and fluoxetine (Prozac) in the past. The increased buspirone blood level yielded sedation.Psychiatry Case Vignettes 71 buspirone (BuSpar). May 1999). 2001 Greenblatt DJ. Risperidone is a substrate of 2D6 and 3A4 (DeVane and Nemeroff 2001). von Moltke LL. Harmatz JS. 1999. J Clin Psychopharmacol 19(suppl):23S–35S. 1999 Kivisto KT. 1997 . which led to increased blood levels of these substrates. 1997). Fluoxetine (in concert with its active metabolite. 2002). He was frequently pacing the halls. and drug interactions. abruptly fall asleep. Lamberg TS. the patient was experiencing a peculiar state of alternating and mixed sedation and severe restlessness. Stevens and Wrighton 1993). et al: Human cytochromes and some newer antidepressants: kinetics. References DeVane CL. Clin Pharmacol Ther 62:348–354. Discussion This is an example of an inhibitor added to two substrates. 45 mg/day. and this had been effective. and a remission of the sedation and akathisia. but he had also begun to report increasing dysphoria. At various times he would stop pacing. a return to the baseline blood levels of both risperidone and buspirone. norfluoxetine) is a strong 2D6 inhibitor and a moderate 3A4 inhibitor (Greenblatt et al. He had achieved significant relief from his paranoid delusions and generalized anxiety on this regimen. Kantola T. personal communication. to his regimen. metabolism. Nemeroff CB: An evaluation of risperidone drug interactions. anhedonia. and within 2 weeks these symptoms cleared (J. et al: Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole. whereas the increased risperidone blood level caused akathisia. deLeon. Within 10 days. so the patient’s psychiatrist decided to again add fluoxetine. on average. and decreased appetite. he discontinued the fluoxetine.

where she received supportive treatment with antipyretics and lorazepam (Ativan). with little clinical benefit. diarrhea. Within another 3 days. Venlafaxine. 2001). still considerable serotonin reuptake inhibitor activity combined with that of venlafaxine. and fluoxetine/ norfluoxetine is a potent 2D6 inhibitor (Stevens and Wrighton 1993). Oesterheld. is an equally potent serotonin reuptake inhibitor. 1993 PREMATURE CROSSOVER A 23-year-old woman with a history of melancholic major depression was given fluoxetine (Prozac). the patient was started on venlafaxine XR.R. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. and she was admitted to the medical floor of a nearby hospital. Scordo MG. She was discharged without complications 2 days later. but its average half-life is 17 days (Brunswick et al. personal communication.72 Drug–Drug Interaction Primer Spina E. The venlafaxine was discontinued. at 150 mg/day. Thus. which was titrated to a dosage of 60 mg/day. but she waited another 4 weeks before doing so (J. et al: Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction. Three days after abruptly discontinuing the fluoxetine. A likely contributor to this serotonin syndrome was the pharmacokinetic interaction between fluoxetine and venlafaxine. J Pharmacol Exp Ther 266:964– 971. Discussion This is a combined example of a substrate added to an inhibitor and excessive pharmacodynamic synergy. the patient experienced disturbing myoclonus along with flushing. Venlafaxine is predominantly a substrate of 2D6 (Wyeth Laboratories 2002). Thus. the 5–6 days between the discontinuation of the fluoxetine and the time it took for venlafaxine to reach steady state was not sufficient to prevent the excessive additive effects of fluoxetine’s. and fever. 2002 Stevens JC. the considerable amount of norfluoxetine that was present when venlafax- . 150 mg/day. Her psychiatrist decided to embark on a trial of venlafaxine (Effexor). The end result was a mild to moderate central serotonin syndrome leading to an avoidable hospitalization. norfluoxetine. Avenoso A. Fluoxetine is a potent selective serotonin reuptake inhibitor with an average half-life of 1–3 days (Eli Lilly/Dista Pharmaceuticals 2001). and especially norfluoxetine’s. also functions as a potent serotonin reuptake inhibitor. fluoxetine’s major metabolite. May 2002). J Clin Psychopharmacol 22:419–423. However. She did eventually try venlafaxine again.

References Brunswick DJ. 2. PA. This led to a sharp increase in the blood level of lamotrigine. Over the next several days. 2001 Stevens JC. Eli Lilly/Dista Pharmaceuticals. 200 mg/day (blood level. Thus. so her psychiatrist decided to introduce sertraline (Zoloft) at a low dosage (25 mg/day) into her regimen. Amsterdam JD. When she reported this to her psychiatrist. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. 2002 A LITTLE GOES A LONG WAY A 36-year-old woman with bipolar I disorder had been stably maintained on lamotrigine (Lamictal). 1999). 1993 Wyeth Laboratories: Effexor (package insert). for the past 18 months.Psychiatry Case Vignettes 73 ine reached steady state was still able to strongly inhibit 2D6. and insomnia began to develop. leading to a greater-than-expected blood level of venlafaxine and thereby increasing the likelihood of an adverse event such as a serotonin syndrome. which was found to be 5. J Clin Psychopharmacol 21:616– 618.5 µg/mL). Sertraline. 2001 Eli Lilly/Dista Pharmaceuticals: Prozac (package insert). is an inhibitor of UGT1A4 (Kaufman and Gerner 1998). IN. et al: Fluoxetine and norfluoxetine plasma levels after discontinuing fluoxetine therapy. the psychiatrist discontinued the sertraline and started the patient on citalopram (Celexa). anhedonia.1 µg/mL. the patient developed increasing lethargy and confusion. Discussion This is an example of an inhibitor added to a substrate. a doubling in this case (Kaufman and Gerner 1998). Fawcett J. Lamotrigine is metabolized primarily through phase II glucuronidation. the patient’s resulting symp- . J Pharmacol Exp Ther 266:964–971. with no further difficulties of this nature. Some persistent dysphoria. he ordered another lamotrigine blood level. Philadelphia. Indianapolis. specifically by the uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 enzyme (Hiller et al. the addition of sertraline (and at a low dosage at that) significantly impaired the ability of UGT1A4 to metabolize the lamotrigine. After consulting with the affiliated hospital’s pharmacist. Wyeth Laboratories. which qualified as a long period of stability for this patient. Because the final lamotrigine blood level was not terribly high (5.1 µg/mL). seemingly unique among the selective serotonin reuptake inhibitors.

which was being well controlled with lithium (Eskalith). et al: Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Lithium is entirely renally excreted. Nguyen N. he decided to contact his psychiatrist. in checking lamotrigine levels on patients that I and my colleagues have placed on sertraline. This would have been more expected if valproate had been the added agent. His orthopedist prescribed a nonsteroidal anti-inflammatory drug (NSAID). Over the next several days. Gerner R: Lamotrigine toxicity secondary to sertraline. He was well aware of the importance of good hydration while taking lithium. developed severe tendinitis in his right ankle 2 weeks before a major triathlon for which he had been training for months. 50 mg tid.” He also noted that he was urinating more frequently. However. until after the triathlon. References Hiller A.5 mEq/L. 1999 Kaufman KR. Seizure 7:163– 165. she had him report for an immediate lithium blood level. She asked the patient about any recent changes in his medication regimen. with the exception of aspirin and sulindac (Clinoril).8 mEq/L). the patient noted that he felt increasingly “spacey. we have observed this interaction only inconsistently. When he developed a frank tremor that made it difficult for him to feed himself or write. it is worth noting that only 25 mg/day of sertraline was able to double the lamotrigine blood level. which was found to be 1. All NSAIDs (including indomethacin). 0. to elevate lamotrigine blood levels. but between sweating during his training and his frequent urination. Drug Metab Dispos 27:605– 612. indomethacin (Indocin). The change in lithium blood level can be quite variable and difficult to predict. yet sertraline appears.74 Drug–Drug Interaction Primer toms were not too dramatic or distressing. the important task of hydration became harder to maintain. 900 mg/day (blood level. Ragheb 1990). Strassburg CP. The proposed mechanism for this interaction is that NSAIDs . so close observation and frequent lithium levels are warranted. and therefore a variety of medications that alter renal function can alter the rate of lithium excretion. 1995. at least some of the time. will often elevate lithium blood levels (Finley et al. Discussion This is an example of mild NSAID-induced lithium toxicity. On hearing that he was taking indomethacin on a regular basis. However. 1998 THE TREMULOUS TRIATHLETE A 31-year-old triathlete with bipolar I disorder.

He was becoming preoccupied with enucleating himself and thus removing this device. lithium carbonate. the patient’s mild dehydration also likely contributed to his emerging lithium toxicity. Discussion This is an example of a mild hypertensive episode induced by a monoamine oxidase inhibitor (MAOI)–clozapine interaction. Despite this broad-spectrum regimen. After 1 week at this dosage of clozapine. however.0 mEq/L). nonsulindac NSAID. so the psychiatrist decided to add clozapine (Clozaril) to his regimen. 1997). benztropine (Cogentin). Because the patient was now receiving two agents that were notorious for producing orthostatic hypotension (phenelzine and clozapine). 15 mg tid. 900 mg/day. Peabody CA: Clinical relevance of drug interactions with lithium.Psychiatry Case Vignettes 75 inhibit prostaglandin synthesis in the kidney. lithium levels should be closely monitored and lithium dosages should perhaps even be slightly lowered in anticipation of this interaction. Bull Acad Natl Med 181:685–697. Warner MD. References Finley PR. was being unsuccessfully treated with the following medications: fluphenazine (Prolixin). 1997 Ragheb M: The clinical significance of lithium–nonsteroidal anti-inflammatory drug interactions. 1 mg/day. Clin Pharmacokinet 29:172–191. et al: Mechanisms of drug interactions with renal elimination of lithium (in French). especially in those individuals whose maintenance lithium blood levels are on the high end of the maintenance range (0. Barthelmebs M. 1995 Imbs JL. he continued to endorse paranoid delusions that he was being followed and harassed by the Federal Bureau of Investigation and Central Intelligence Agency and that they had implanted a tracking device behind his left eye. and the patient’s blood pressure returned to baseline (K.8–1. the psychiatrist was vigilant in monitoring the patient’s orthostatic blood pressure readings twice each day. Whenever a patient who is taking lithium is placed on a standing regimen of a nonaspirin. Danion JM. 10 mg/day. bipolar type. July 2002). personal communication. 1990 BAFFLING HYPERTENSION A 47-year-old man with schizoaffective disorder. . his blood pressure had risen from a typical 115/80 mm Hg to 180/105 mm Hg. and phenelzine. the patient’s blood pressure readings began to climb. titrating to a dosage of 400 mg/day. The clozapine was gradually tapered and discontinued. In a few days. Walters. J Clin Psychopharmacol 10:350–354. In this case. thus interfering with the excretion of lithium (Imbs et al.

et al: The effect of clozapine on plasma norepinephrine: relationship to clinical efficacy. both phenelzine and clozapine often produce orthostatic hypotension (Kaplan and Sadock 1998). the inconvenience of hourly trips to the bathroom. Williams and Wilkins. 1995 DIABETES INSIPIDUS DIFFICULTIES A 23-year-old man was diagnosed with bipolar I disorder after his first unequivocal manic episode. He also experienced constant thirst. 1998 Taylor D. also blocks central α2-adrenergic receptors (Kaplan and Sadock 1998). Clozapine. interrupted sleep. in addition to its multiple dopamine and serotonin receptor blockade effects. As an MAOI. The surprise for the treatment team lay in the fact that the combination of two typically orthostasis-producing agents resulted in a hypertensive state. norepinephrine. (1994) found that the administration of clozapine led to a mean 471% increase in plasma norepinephrine levels. He was initially treated with lithium (Eskalith). blockade of this receptor by clozapine will lead to increased presynaptic release of norepinephrine. mitigated by the hypotension-producing α1 blockade profiles of both compounds.9 mEq/L). Insofar as this is the noradrenergic system autoreceptor. Sadock B: Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. who also had bipolar disorder. MD. Baltimore. and dopamine) to produce hypertensive crises. 8th Edition. and fortunately. References Breier A. he was experiencing a side effect his father had not experienced. He asked his psychiatrist for help with this problem. which can interact with agents that increase the availability of catecholamines (epinephrine. Buchanan RW. Faivre F: Clozapine-induced hypotension treated with moclobemide and Bovril. Br J Psychiatry 167:409–410. In one case series. His urinary output was about 2. 50 mg/day.76 Drug–Drug Interaction Primer By virtue of α1-adrenergic blockade. 1994 Kaplan H. phenelzine inhibited the breakdown of this increased amount of norepinephrine.5 L/day. Although this thiazide diuretic exerted its . and even occasional nocturnal enuresis. Breier et al. Neuropsychopharmacology 10:1–7. and his psychiatrist added hydrochlorothiazide. in no small part because his father. However. had enjoyed a profound and sustained response to this medication over the years. 900 mg/day (blood level. Reveley A. requiring the patient to engage in an onerous amount of fluid repletion. 1995) that was likely. 0. phenelzine is an MAOI. Waltrip RW 2nd. leading to an increase in blood pressure (Taylor et al. Although the lithium was as effective for the patient as it had been for his father.

Finley et al. 8th Edition.4 mEq/L.9 mEq/L). Sadock B: Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/ Clinical Psychiatry. Warner MD. 0. and 1. 250 mg/day. over the next 3 days he experienced increasing tremor. Discussion This is an example of lithium toxicity caused by a sodium-depleting agent. Mack JE. von Riotte AB. the kidney confuses the two ions and thus acutely decreases its clearance of lithium as well (Kaplan and Sadock 1998). 1985 Crabtree BL. ataxia. In this case. dysarthria. Grossly speaking. Clin Pharmacokinet 29:172–191. Williams and Wilkins. A better choice for decreasing urine output in lithium-induced diabetes insipidus would have been amiloride (Midamor). N Engl J Med 312:408–414. 1991 Finley PR. MD. et al: Comparison of the effects of hydrochlorothiazide and furosemide on lithium disposition. Peabody CA: Clinical relevance of drug interactions with lithium. et al: Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. and sedation. 1985). 1995). This retention of lithium then produces an increase in the lithium blood level. because the baseline lithium level was relatively high (0. 1995 Kaplan H. However. usually by roughly 25%–40% (Crabtree et al. 1991. The psychiatrist instructed the patient to go to the emergency room to obtain a lithium blood level. the kidney tries to compensate for this effect by retaining sodium at other portions of the nephron. she was recently hospitalized because of a breakthrough manic episode.Psychiatry Case Vignettes 77 anticipated paradoxical effect of decreasing the patient’s urine production.9 mEq/L) of lithium. Baltimore. Am J Psychiatry 148:1060–1063. Because lithium and sodium are both monovalent cations. Gaviria M. Johnson CD. she declined the offer of an ad- . References Batlle DC.200 mg/day (blood level. Because of her aversion to the concept of antipsychotic medication. 1998 RASH DECISION (I) A 30-year-old woman with a history of bipolar I disorder had been stably maintained on lamotrigine (Lamictal). Hydrochlorothiazide causes increased sodium excretion at the distal convoluted tubule of the nephron. the resulting blood level produced a state of mild lithium toxicity. which accomplishes the same decrease in urine production but generally without significant changes in lithium or potassium levels (Batlle et al. which was 1.

et al: Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Nguyen N. but within 1 week she reported feeling dizzy. and the glucuronidative metabolism of divalproex (again. sedated. 2002). Thus the addition of the divalproex significantly impaired the ability of the 1A4 enzyme to efficiently metabolize the lamotrigine. February 2001). GlaxoSmithKline 2004). Prim Psychiatry 9:28–57. The likely explanation is that lamotrigine seems to have some weak induction effects on glucuronidation enzymes (not as yet formally characterized). Greenville. titrated to a dosage of 1. and “slowed. NC. a diffuse rash appeared on her upper arms. Ther Drug Monit 24:91–103. 92 µg/mL). Divalproex is an inhibitor of this same glucuronidation enzyme (Hachad et al. Lamotrigine is metabolized primarily through phase II glucuronidation. Stahle L: Lamotrigine drug interactions in a TDM material. Ragueneau-Majlessi I. References Bottiger Y. even though the dosage of lamotrigine had not been changed (Bottiger et al.” Additionally.B. Ther Drug Monit 21:171–174. 1999). 1999 DeVane CL. Sandson. Discussion This is an example (primarily) of an inhibitor added to a substrate. 2002 Hiller A.78 Drug–Drug Interaction Primer junctive atypical antipsychotic and instead consented to the addition of divalproex sodium (Depakote). because they can be the precursor of a full Stevens-Johnson syndrome or toxic epidermal necrolysis. Her manic symptoms gradually remitted. In addition to the elevation of lamotrigine blood levels by divalproex. Drug Metab Dispos 27:605–612. which led to an increase in the blood level of lamotrigine. and in a few days the rash began to fade and the patient continued to improve clinically (N. The psychiatrist immediately discontinued the lamotrigine. not yet well characterized) is accordingly enhanced. 1999). specifically by the 1A4 enzyme (Hiller et al. Strassburg CP. it appears that adding lamotrigine to divalproex will consistently decrease divalproex blood levels by roughly 25% (DeVane and Nemeroff 2002. Svensson JO. 2002 GlaxoSmithKline: Lamictal (package insert). Nemeroff CB: 2002 guide to psychotropic drug interactions. Lamotrigine rashes generally warrant immediate discontinuation of this medication.000 mg/day (blood level. 1999 . yielding a modest decrease in the blood levels of divalproex. Levy RH: New antiepileptic drugs: review on drug interactions. This rapid rise in the lamotrigine blood level caused the patient to experience the symptoms of sedation and mild confusion as well as the emergence of a rash. 2004 Hachad H. self-report. GlaxoSmithKline.

At that point. and he decided to consciously increase his intake of caffeinated beverages (coffee. His psychiatrist tried to counsel him and help him accept and adapt to the changes that treatment was producing for him. carbonic anhydrase inhibitors. After another week had passed. 900 mg/day (blood level. He felt so good that he did not even mind taking the lithium. He was tempted to skip it but decided to go and say goodbye before his flight the next day.3 mEq/L. Gray and Gray 1989. tea. including the “letdown” of stable euthymia. This increased excretion of lithium led to a decrease in the lithium blood level and the recurrence of a manic episode of moderate to severe intensity. Two weeks later. including sodium and lithium. who artfully convinced the patient to defer his plans and accompany him to the day hospital.75 mEq/L). the patient did indeed feel more energetic and less blunted. whereas xanthines. Lithium is primarily renally excreted. Kaplan and Sadock 1998). Caffeine. . The patient remained unsatisfied. which he continued to do faithfully. Encouraged by this early result. the patient had one of his scheduled appointments with his psychiatrist. as well as other xanthines such as theophylline. The patient ebulliently shared his future plans with the psychiatrist. 0. but that seemed only a minor impediment. when he would frequently cycle into hypomanic episodes. Within 3 days. where a lithium blood level was found to be only 0. however. Discussion This is an example of the role of caffeine in decreasing lithium blood levels. soda) and over-the-counter caffeine tablets in the hope that he could recapture some of his lost vigor. he had so much energy that he needed only 2–3 hours of sleep each night to feel completely refreshed. However.Psychiatry Case Vignettes 79 MORE THAN HE BARGAINED FOR A 33-year-old man with recently diagnosed bipolar I disorder had remained essentially euthymic for the past 4 months while taking lithium. He did not speak any French. It is worth noting that different diuretic agents have different effects on lithium excretion. acts as a diuretic by increasing the glomerular filtration rate and renal blood flow. he consistently complained that he felt “blunted” and “less alive” than in his pre-lithium days. he felt he was doing so well that he was going to quit his job as a cook and travel to Paris to open his own bistro. 1995. Thiazide diuretics increase lithium levels (see “Diabetes Insipidus Difficulties” earlier in the chapter). which results in increased excretion of most solutes. and other osmotic diuretics will reliably decrease lithium levels (Finley et al. the patient adhered to this unilateral plan of high caffeine intake.

she became acutely anxious and agitated. 2001 Pfizer: Nardil (package insert). and “twitchy. GlaxoSmithKline 2001. Peabody CA: Clinical relevance of drug interactions with lithium. these symptoms basically remitted by the morning. Peck R: Dextromethorphan: an overview of safety issues. Gray LK: Nutritional aspects of psychiatric disorders. she contracted a bad case of the flu. New York.” as she described it. GlaxoSmithKline. 2003 . nauseated. she purchased some NyQuil and ingested a dose before going to bed. a monoamine oxidase inhibitor (MAOI). 1989 Kaplan H. diaphoretic. Baltimore. References Bem JL. Research Triangle Park. congestion. but safe clinical practice entails a low threshold for mobilizing intensive medical interventions when this syndrome is suspected. Sadock B: Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/ Clinical Psychiatry. which was relatively mild. 60 mg/day. and dextromethorphan (contained in NyQuil). hospitalization was not necessary. Discussion This is an example of a substrate added to an inhibitor. 1992 GlaxoSmithKline: Parnate (package insert). In this case. In this case. Warner MD. Her rhinitis. 8th Edition. which has “serotomimetic” properties. NC. 1998 OVER-THE-COUNTER CALAMITY A 44-year-old woman with a long-standing atypical depression had done well for the past 2 years since she began taking tranylcypromine (Parnate). This combination of factors increased physiological serotonin tone to the extent that a central serotonin syndrome was produced (Bem and Peck 1992. febrile (again). which defines one of the functions of an MAOI. Instead of getting a good night’s sleep.80 Drug–Drug Interaction Primer References Finley PR. and sore throat made it difficult for her to sleep. MD. Pfizer 2003). Williams and Wilkins. Clin Pharmacokinet 29:172–191. and when she read the ingredients on the NyQuil box she realized her mistake. Fortunately. Drug Saf 7:190–199. a mild central serotonin syndrome arose from the combination of tranylcypromine. One winter. Pfizer. J Am Diet Assoc 89:1492–1498. In an exhausted and inattentive state. this synergized with the prevention of the breakdown of serotonin. 1995 Gray GE. When the dextromethorphan increased the availability of serotonin (a monoamine).

resulting in a decrease in the blood level of lamotrigine. Discussion This is an example of an inducer added to a substrate. She unfortunately required hospitalization for a breakthrough manic episode. Oxcarbazepine is a moderately strong inducer of glucuronidation enzyme 1A4 (May et al. he also provided lorazepam (Ativan) for control of agitation. Because both divalproex sodium (Depakote) and carbamazepine (Tegretol) are notorious for altering lamotrigine blood levels. 1999). Nguyen N. Although this is not a huge effect. However. it accounted for lamotrigine’s loss of mood stabilizer efficacy (for the depressive pole) and thus the patient’s “mood instability” following the addition of oxcarbazepine. Her psychiatrist responded by (gradually) increasing the dosage of lamotrigine to 400 mg/day. Lamotrigine is primarily metabolized through phase II glucuronidation. and she was discharged after a 10-day stay in the hospital. and titrated the dosage to 600 mg bid. Strassburg CP. Drug Metab Dispos 27:605–612. 3 weeks later. Although it is not the robust 3A4 inducer that carbamazepine is. et al: Retigabine N-glucuronidation and its potential role in enterohepatic circulation. 1999 . The patient’s manic symptoms gradually improved. 1999). having heard that it was an effective antimanic agent and that it reportedly did not interact with other medications as carbamazepine did. Studies have demonstrated that the addition of oxcarbazepine to lamotrigine can decrease lamotrigine blood levels by roughly 30% on average (May et al. 300 mg bid. her psychiatrist decided to try oxcarbazepine (Trileptal). 1999). This led to an increase in the amount of this enzyme that was available to metabolize the lamotrigine. References Hiller A. oxcarbazepine is certainly not devoid of any drug interactions.” The psychiatrist nicely compensated for this effect by increasing the lamotrigine dosage from 250 mg/day to 400 mg/day.Psychiatry Case Vignettes 81 MOOD DESTABILIZATION A 29-year-old woman with rapid cycling bipolar I disorder had responded well to lamotrigine (Lamictal) monotherapy at a dosage of 250 mg/day. specifically by the 1A4 enzyme (Hiller et al. He had the patient start taking oxcarbazepine. another “mood stabilizer. even though the lamotrigine dosage had not been decreased. which did produce a remission of her depressive symptoms. the patient began to experience an emergence of depressive symptoms. She had a history of poorly tolerating lithium and antipsychotic medications (even atypical agents).

500 mg/day (blood level. and ammonia level. specifically including 1A2. 2004. Carbamazepine is an inducer of multiple P450 enzymes.2 µg/mL. Later that day. 2 mg bid. Bottiger et al. His psychiatrist decided to add carbamazepine and thus go to “triple therapy. clonazepam (Klonopin). 8. Spina et al. 1. 50 mg/day. Significant test results included the following levels: divalproex. 2004). 2C9. 1988. alanine aminotransferase.” Over a 2-week period. many laboratory studies were obtained. Parker et al. but his bipolar illness had not responded to the following regimen: lithium. he had his first grand mal seizure in 2 years. It also induces uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 (Arana et al. Ucar et al. the most likely means by which carbamazepine influences the metabolism of divalproex is through the increased production . He reported the emergence of auditory hallucinations and seemed preoccupied with the observation cameras on the unit. 1999. Discussion This is a mixed example of an inducer (carbamazepine) added to a substrate (divalproex) and a substrate (carbamazepine) added to an inhibitor (divalproex).7 µg/mL). First. 48 µg/mL. 120 µg/mL). The next morning. and 3A4. the metabolism of divalproex is exceedingly complex. involving multiple P450 enzymes and phase II glucuronidation. Miners and Birkett 1998.0 mEq/L). the carbamazepine was titrated to 800 mg/day (blood level. 1998. Rambeck et al. carbamazepine. 1996. After 2 weeks at this dosage of carbamazepine. 1. Ther Drug Monit 21:175–181. rapid-cycling bipolar I disorder and a comorbid seizure disorder had been consistently seizure free.050 mg/day (blood level. Of these possible points of interaction. and the staff observed that his gait had become unsteady. 1 mg bid. 1. and liberating 50 or more metabolites (Pisani 1992)! Blood levels of free valproate are also influenced by the presence of other strongly plasma protein–bound compounds. 82 IU/L (previously within normal limits). the patient was increasingly lethargic and irritable. Lucas et al. 1999 DISEQUILIBRIUM A hospitalized 28-year-old man with treatment-resistant. 65 µmol/L. divalproex sodium (Depakote).82 Drug–Drug Interaction Primer May TW. loxapine (Loxitane). Jurgens U: Influence of oxcarbazepine and methsuximide on lamotrigine concentrations in epileptic patients with and without valproic acid comedication: results of a retrospective study. 9. 1996. Faucette et al. 2B6. and benztropine. 1998. Rambeck B.

and/or seizure activity. .11-epoxide (Spina et al.) Although such an increased metabolite level in the face of enzymatic induction may at first seem counterintuitive. 4-ene-valproic acid. likely played a large role in the patient’s ataxia. Staines et al. irritability. (The production of 4-ene-valproic acid is increased when divalproex is coadministered with agents that artificially induce its metabolism. Blood levels of carbamazepine-10. This metabolite may lead to clinical carbamazepine toxicity because of its additive effects on the nervous system exerted by its carbamazepine-like pharmacological activity. when considered in addition to the carbamazepine. 2C8. with 1A2. Divalproex is an inhibitor of 2C9 (Wen et al. carbamazepine is primarily a 3A4 substrate. due to the increased production of carbamazepine10. and seizure. Jann et al. 1996). such as phenytoin. 1988). 1997. however. the formation of this metabolite.11-epoxide will often double when valproic acid is added (G. the enzyme responsible for metabolizing and clearing the neurotoxic and pharmacologically active carbamazepine metabolite carbamazepine-10. personal communication. thus leading to accumulation of this metabolite. 2004). probably through inhibition of P450 2C9. The accumulation of this hepatotoxic 4-ene-valproic acid metabolite likely explains this patient’s increased alanine aminotransferase and hyperammonemia. lethargy. These tests must be specifically requested. Divalproex does not usually strongly affect the metabolism of carbamazepine itself except in that through its 2C9 inhibition it may contribute to modestly raising carbamazepine levels. 1996.Psychiatry Case Vignettes 83 (induction) of glucuronidation enzymes. leading to a roughly 60% decrease in valproate blood levels (Bernus et al. April 2002). 2B6. It is important to note that this state of clinical carbamazepine toxicity. 1990]. emerging paranoia. and carbamazepine [Levy et al. Inhibition of epoxide hydrolase by divalproex leads to the accumulation of the carbamazepine-10. lethargy. 2001) and glucuronidation enzyme 1A4 (Hachad et al. and phase II metabolism (UGT2B7) making minor contributions to carbamazepine’s metabolism (Pearce et al. the coadministration of carbamazepine and divalproex leads to the increased production of a hepatotoxic metabolite. However. The main divalproex effect of relevance to this case. Thus. 2E1.11-epoxide metabolite. Second. Spina et al. it represents the enhanced generation of this toxic metabolite through the artificial “pulling” of divalproex’s metabolism through atypical pathways at a greater than usual rate. 2002). phenobarbital. and therefore possibly some component of the patient’s unsteadiness. Krause.11-epoxide. 2C9. Laboratories do not typically test for the presence of either 4-ene-valproic acid or carbamazepine-10. which is faster than the body can eliminate it. is usually accompanied by carbamazepine blood levels that are in the normal range.11-epoxide. 2002. is divalproex’s ability to inhibit epoxide hydrolase.

1998 Parker AC. Wang H. 1988 Levy RH. Preston T. et al: Increased valproate serum concentrations upon carbamazepine cessation. et al: Effects of polytherapy with phenytoin. Wolf P: Pharmacokinetic interactions of the new antiepileptic drugs. Eur J Clin Pharmacol 54:639–643. J Clin Psychiatry 49:448– 449. 1996 Staines AG. 2002 Jann MW. 2004 Hachad H. Eur J Clin Pharmacol 59:879– 882. J Pharmacol Exp Ther 311:1131–1137. et al: In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9). Br J Clin Pharmacol 45:176– 178. 1996 Spina E. Rettenmeier AW. 2002 Pisani F: Influence of co-medication on the metabolism of valproate. Br J Clin Pharmacol 52:547–553. Clin Pharmacol Ther 48:225– 235. 1998 Pearce RE. 1992 Rambeck B. et al: Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test. 2001 . Gilfillan DJ. Anderson GD. Pritchard P.and 3-hydroxylated metabolites. 1988 Bernus I. Clin Pharmacokinet 31:309–324. Leeder JS: Pathways of carbamazepine bioactivation in vitro. Neuvonen M. et al: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. Svensson JO. Drug Metab Dispos 32:348–358. et al: The mechanism of the carbamazepinevalproate interaction in humans. Kivisto KT. Luurila H. Burchell B: N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. Br J Clin Pharmacol 44:21–27. Coughtrie MW. Molloy M. 1998 Miners JO.84 Drug–Drug Interaction Primer References Arana GW. Ther Drug Monit 21:171–174. Vakkalagadda GR. Birkett DJ: Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. 2004 Wen X. Fidone GS. Pisani F. carbamazepine. 2004 Ucar M. Epstein S. and stiripentol on formation of 4-ene-valproate. Hamilton GA. a hepatotoxic metabolite of valproic acid. Wang JS. Stahle L: Lamotrigine drug interactions in a TDM material. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Epilepsia 29:578–581. Specht U. Drug Metab Dispos 30:1170–1179. 1990 Lucas RA. I: characterization of human cytochromes P450 responsible for the formation of 2. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. 1999 Faucette SR. Hooper WD. Ther Drug Monit 24:91–103. Br J Clin Pharmacol 45:525–538. Pharmaceutisch Weekblad (Scientific Edition) 14:108–113. Bergstrom RF: A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism. Dickinson RG. Levy RH: New antiepileptic drugs: review on drug interactions. 1997 Bottiger Y. Israel MK. Ragueneau-Majlessi I. Clin Pharmacokinet 31:198–214.

Phenytoin is an inducer of multiple enzymes. and instructed the patient to take these medications at these dosages for the next 2 weeks or until the patient developed side effects from these changes. First. his typical phenytoin blood level was roughly 17 µg/mL. the patient was becoming manic again. His sister contacted the psychiatrist. This led to a roughly 50% decrease in the measured total divalproex blood level (Pisani 1992) and a decrease . requiring less sleep and hatching grandiose and expensive plans. Phenytoin and divalproex blood levels were also obtained. and glucuronidation enzyme 1A4. and promptly advised him to stop this medication. Discussion This is a complex example of mixed plasma protein displacement.500 mg/day (blood level. 2C9. that had been prescribed for his seizure disorder prior to his recent hospitalization. and olanzapine (Zyprexa). his sister did note that his “eyeballs seemed to twitch” at times. 2C19. olanzapine is a substrate of 1A2. 3A4. 20 mg/day. 2C19. 2002. Raucy 2003). 1999. P450 inhibition. 400 mg/day. 1998. 2D6. Five days after resuming the phenytoin. Without contacting his psychiatrist or neurologist. specifically including 2C9. and glucuronidation enzyme 1A4 (Callaghan et al. respectively. discovered that he had resumed his phenytoin. 105 µg/mL). Linnet 2002). 1999. the metabolism of divalproex is exceedingly complex. thus yielding more efficient metabolism of both the divalproex and the olanzapine. but this was not so severe as to be troublesome. adding the phenytoin led to the increased production of 3A4. Two weeks later. he seemed more sedated than he had expected. his sister presented him with the phenytoin (Dilantin). respectively. involving multiple P450 enzymes and phase II glucuronidation. Chetty et al. the patient again began taking the phenytoin.000 mg/day and 30 mg/day. Therefore. His divalproex blood level also returned to its baseline. and he then returned to his baseline dosages of divalproex and olanzapine without incident. and liberating 50 or more metabolites (Pisani 1992)! Also. Gibson et al. The patient’s manic symptoms gradually receded.Psychiatry Case Vignettes 85 HIGH–LOW A 26-year-old man with bipolar I disorder and a seizure disorder was released from the hospital after successful treatment of a manic episode with a new regimen: divalproex sodium (Depakote). and uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 (Bottiger et al. The next 2 weeks progressed uneventfully. and induction of glucuronidation. One week after discharge. who met with the patient. He also increased the dosages of divalproex and olanzapine to 2. with results of 23 µg/mL and 62 µg/mL. However. 1. At 400 mg/day.

2002. Ragueneau-Majlessi I. Cytochrome P450 2C9 does not merely contribute to the metabolism of valproate. Stahle L: Lamotrigine drug interactions in a TDM material. 1990). Ptak LR. Wen et al. Levy RH: New antiepileptic drugs: review on drug interactions. which correlates with observations of increased incidence of hepatotoxicity when combining valproate with cytochrome P450 inducers such as phenytoin. Phenytoin and divalproex are also both highly bound to plasma proteins (Kodama et al. One study found that this combination led to a twofold increase in levels of this metabolite. Second. so this combination led to increases in the free fraction of both drugs. Toxicology 181–182:199–202. This occurs because it is the metabolism of the free fraction that is being inhibited. In this case.) Additionally. el-Sankary W. 1999 Chetty M. the marked increase in the free/active fraction of phenytoin led to the development of sedation and nystagmus. These two factors (mutual displacement and inhibition of 2C9 by valproate) combined to produce a modest increase in the total phenytoin level but most likely a disproportionate increase in the free phenytoin concentration (Lai and Huang 1993). which unfortunately was not checked in this case. but it is also one of the enzymatic pathways that leads to the production of the hepatotoxic 4-enevalproate metabolite (Sadeque et al. phenytoin is a substrate primarily of 2C9 and 2C19. (Although this has not been rigorously studied. carbamazepine. mutual displacement between valproate and phenytoin and corresponding increases in the free fraction of both drugs should yield even greater than normal susceptibility of valproate to induction by phenytoin and disproportionate decreases in the free concentration of valproate relative to decreases in total valproate concentrations. et al: Olanzapine: pharmacokinetic and pharmacodynamic profile. References Bottiger Y. Bergstrom RF. Seymour MA: Phenytoin autoinduction. and phenobarbital (Levy et al. there is another aspect of the phenytoin’s induction of valproate that can prove clinically significant. Miller R. 2001). Thus. 2001). 1998 Gibson GG. phenytoin’s induction of this enzyme not only leads to decreases in valproate concentrations but also generates increases in this hepatotoxic metabolite. 2002 Hachad H. 2002 . Divalproex is an inhibitor of 2C9 and an inhibitor of glucuronidation enzyme 1A4 (Hachad et al. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. 1997). Ther Drug Monit 20:60– 62. 2000. 1999 Callaghan JT. Ther Drug Monit 24:91–103. Svensson JO.86 Drug–Drug Interaction Primer in the blood level of olanzapine. Clin Pharmacokinet 37:177–193. Ther Drug Monit 21:171–174.

Following a heated divorce. 2001 THE ZEBRAS ARE LOOSE A 46-year-old man with gastroesophageal reflux disease was taking metoclopramide (Reglan). Biopharm Drug Dispos 14:365–370. Discussion This is an example of excessive pharmacodynamic synergy. Kivisto KT. Drug Metab Dispos 31:533–539. Korzekwa KR. and irritability. Kodama H. J Pharmacol Exp Ther 283:698–703. myoclonus. he became acutely depressed and was prescribed venlafaxine (Effexor). et al: In vivo binding characteristics of phenytoin to serum proteins in monotherapy for adults with epilepsy. 2003 Sadeque AJ. Kuranari M. Venlafaxine is a serotonin reuptake inhibitor (a serotonin reuptake inhibitor at low doses. vomiting. 1992 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. diaphoresis. carbamazepine.Psychiatry Case Vignettes 87 Kodama H. Br J Clin Pharmacol 52:547–553. which leads to increased availability of serotonin and thus serotonergic activity. and stiripentol on formation of 4-ene-valproate. Hum Psychopharmacol 17:233– 238. 1993 Levy RH. Rettenmeier AW. Fisher MB. which was titrated up to a dosage of 225 mg/day. He contacted his new psychiatrist. who advised him to report to the nearest emergency room.or age-related binding characteristics of valproic acid to serum proteins in adult patients with epilepsy. which produced a central serotonin syndrome. Am J Ther 7:359–363. et al: Gender. the patient acutely developed flushing. 1997 Wen X. 2001 Lai ML. 15 mg qid. et al: Effects of polytherapy with phenytoin. 2002 Pisani F: Influence of co-medication on the metabolism of valproate. with good success. 1990 Linnet K: Glucuronidation of olanzapine by cDNA-expressed human UDP-glucuronosyltransferases and human liver microsomes. Anderson GD. but it is . et al: Human CYP2C9 and CYP2A6 mediate formation of the hepatotoxin 4-ene-valproic acid. fevers. Wang JS. 2000 Kodama Y. where he was diagnosed with a central serotonin syndrome. Kodama Y. Metoclopramide is generally considered primarily as a dopamine blocker. After 5 days at that dosage. Clin Pharmacol Ther 48:225–235. Shinozawa S. Pharmaceutisch Weekblad (Scientific Edition) 14:108–113. Eur J Pharm Biopharm 52:57–63. Huang JD: Dual effect of valproic acid on the pharmacokinetics of phenytoin. not a selective serotonin reuptake inhibitor). confusion. a hepatotoxic metabolite of valproic acid. et al: In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9).

300 mg qid. This selective serotonergic agonism synergized with the activity of the serotonin reuptake inhibitor (venlafaxine) to produce serotonergic activity so excessive that it reached a toxic level in the form of a central serotonin syndrome (Fisher and Davis 2002). at which point he called 911 and had the patient transported to the nearest emergency room.88 Drug–Drug Interaction Primer also a 5-HT4 agonist (Sommers et al. the patient had become so sedated that her brother could not arouse her from her slumber. 1996 TOO TIRED A 52-year-old woman with generalized anxiety disorder and gastroesophageal disease had been taking alprazolam (Xanax). but the patient was still not satisfied with the results. Several hours later. and cimetidine (Tagamet). for the past 3 months. this interaction is so infrequent that it does not even merit any particular vigilance. Discussion This is an example of excessive pharmacodynamic synergy resulting in excessive sedation. Within 3 days. Kava and alprazolam both act as agonists at the γ-aminobutyric acid receptor. 1 mg tid. should it ever arise. A case of central serotonin syndrome has also been documented in an instance when metoclopramide was combined with sertraline (Fisher and Davis 2002). and they clearly act synergistically in this regard (Izzo and Ernst . van Wyk M: Effects of metoclopramide and tropisetron on aldosterone secretion possibly due to agonism and antagonism at the 5-HT4 receptor. Her anxiety had lessened. The patient decided to take a “natural” remedy for her anxiety to augment the effect of the alprazolam. and her psychiatrist was reluctant to further increase the dosage of alprazolam. 1996). References Fisher AA. Ann Pharmacother 36:67–71. Eur J Clin Pharmacol 50:371–373. Davis MW: Serotonin syndrome caused by selective serotonin reuptake inhibitors–metoclopramide interaction. possibly worsened by a P450 inhibitor–substrate interaction. Unlike the case of combining sumatriptan and sertraline (see “Migraineur” in Chapter 4 of this volume). she became arousable and informed the emergency room staff about her use of kava (Almeida and Grimsley 1996). and to support the notion that we can never prejudge any potential interaction as impossible. She purchased some kava (Piper methysticum) and began taking it per the pharmacist’s instructions. Snyman JR. 2002 Sommers DK. This documented interaction is described here in order to facilitate recognition of this rare event.

Kava’s metabolism has not been well characterized as yet. Albet C. 2000). 1999). another attempt was made to transition from haloperidol. and 1A2 (Martinez et al. his psychiatrist decided to titrate aripiprazole to the target dosage and maintain it at this dosage for at least one month before commencing a very slow haloperidol taper. The cimetidine certainly impaired the ability of 3A4 to metabolize the alprazolam (Dresser et al. given his history of psychotic decompensations with decreases in his haloperidol dosage. However. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Agundez JA. et al: Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2. and CYP3A by H2-receptor antagonists. Aripiprazole was started at 10 mg/day. 1996 Dresser GK. but these had resulted in exacerbations of psychotic symptomatology. Ann Intern Med 125:940–941. the dosage was in- . 2000 Izzo AA. Due to concerns about his eventually developing tardive dyskinesia. Despite recent concerns about kava’s potential for producing hepatotoxicity. leading to a higher alprazolam blood level than would have been expected had the cimetidine not been present. Grimsley EW: Coma from the health food store: interaction between kava and alprazolam. CYP2D6. Initial problems with antipsychotic-induced parkinsonism had led to early attempts to taper and discontinue the haloperidol. the patient became increasingly agitated and aggressive. Over the past several years. his side effects had been fairly well controlled with the benztropine. References Almeida JC. it is still widely used by devotees of alternative remedies as a purported treatment of anxiety and/or insomnia.Psychiatry Case Vignettes 89 2001). Ten days after starting the aripiprazole. 2D6. Drugs 61:2163–2175. Ernst E: Interactions between herbal medicines and prescribed drugs: a systematic review. and 150 mg/day of venlafaxine (Effexor XR). with an increase in paranoia and auditory hallucinations. Spence JD. Clin Pharmacokinet 38:41–57. benztropine (Cogentin). Cimetidine is an inhibitor of 3A4. Clin Pharmacol Ther 65:369–376. Over the next 7 days. 10 mg qhs. but it may be that the cimetidine also impaired the metabolism of kava as well as that of the alprazolam. The magnitude of the resulting sedation in this case may well have been due to the presence of cimetidine. 2001 Martinez C. 1999 DOPAMINE DOUBLE-BIND A 45-year-old male diagnosed with schizoaffective disorder had been stable for the previous 10 years on a regimen of haloperidol (Haldol). 2 mg bid. this time to aripiprazole (Abilify).

The extreme avidity of this drug for the D2 receptor effectively and significantly displaces the original drug from the D2 receptor. 2003). Because this would occur before aripiprazole had been administered for a long enough period to exert its own antipsychotic mechanism of action. decompensation during aripiprazole crossover titrations does not occur most of the time (Casey et al. He eventually reachieved his more functional baseline 3 weeks after the aripiprazole was discontinued. An addition of aripiprazole to haloperidol that produced equimolar central nervous system concentrations of each agent would effectively displace most haloperidol molecules from the D2 receptors to which they were bound. Typical antipsychotics. Once he was hospitalized. even if the original agent is maintained at its baseline dosage. it binds twice as avidly to the D2 receptor as even a robust binder like haloperidol (binding coefficient. as this case and others like it demonstrate. he continued to decompensate over the next several days. aripiprazole is unique even among atypicals (Burris et al. Atypical antipsychotics are thought to employ a broader range of potential antipsychotic mechanisms. aggression. Fortunately. It is considered a prudent principle of crossover titrations that the more gradually they proceed. and psychotic symptoms began to remit. Another unique feature of aripiprazole is the extreme avidity with which it binds to the D2 receptor. 1996). generally exert their primary antipsychotic effect through antagonism of the dopamine D2 receptor. his agitation.90 Drug–Drug Interaction Primer creased to 15 mg/day. Three days after stopping the aripiprazole. the less likely that decompensation will occur due to premature taper of the original agent. eventually requiring hospitalization. such as haloperidol. As a 25%–30% partial dopamine agonist at the D2 receptor. 0. this situation creates a window of vulnerability to decompensation that is difficult to avoid.7) at equimolar concentrations (Bymaster et al. the aripiprazole was discontinued. With a binding coefficient of 0. 2002). However.34 (Otsuka Pharmaceutical 2002). aripiprazole’s ability to displace other antipsychotics from the D2 receptor does make this a more likely concern than with conservative crossover titrations that do not involve aripiprazole. However. Discussion This is an example of displacement from the D2 receptor. Careful clinicians would be well advised to forewarn patients and significant others about this possibility so . However. cross-titrating to aripiprazole makes it very difficult to provide this protection against avoidable decompensation. Conservative clinicians can usually guard against this possibility by waiting at least several weeks after the new agent has been dispensed at target dosages before even initiating the taper of the original agent.

The patient and his psychiatrist collaborated on a plan to transition him to monotherapy with valproate. Two weeks later. He had never received lithium without the venlafaxine. personal communication. whereupon lithium was added to his regimen. However. Initially. Neuropsychopharmacology 14(2):87–96.5 mg/day. Otsuka Pharmaceutical. et al: Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study. 75 mg/day. 900 mg/day (blood level. a novel antipsychotic. he did report marked and troubling polyuria. References Burris KD. the chronology of events implicated this as the most . 250 mg bid. Falcone JF. et al: Radioreceptor binding profile of the atypical antipsychotic olanzapine. 2003 Otsuka Pharmaceutical: Abilify (package insert). divalproex sodium. Since then. 2002 POLYURIA A 46-year-old male with a history of bipolar I disorder had been stably maintained on a combination of lithium. Tokyo. the venlafaxine was stopped altogether. Carson WH. he reported that he was urinating “constantly. Japan. Zuzarte. 0. Calligaro DO. and this was also well tolerated. was added to his regimen. the patient had his first manic episode. Xu C. likely due to dehydration. Although it was not firmly quantified. which he tolerated without difficulty. the patient had been diagnosed with major depressive disorder and was being treated with venlafaxine. After 1 week at this decreased dosage. or discontinuation of the crossover titration can be instituted as soon as possible (E. his urinalyses and serum creatinine values had been consistently normal. the patient experienced disruption of his sleep and dizziness. September 2003). adjunctive treatment measures. and this led him to become more concerned about possible nephrotoxicity associated with long-term lithium treatment. is a highaffinity partial agonist at human dopamine D2 receptors.8 mEq/L) and venlafaxine (Effexor XR).” Over the next several days. Saha AR. After several months of taking the venlafaxine. Although the psychiatrist did not understand how the discontinuation of the venlafaxine might have led to the patient’s polyuria. Molski TF. About 10 years earlier. et al: Aripiprazole. J Pharmacol Exp Ther 302(1):381–389.Psychiatry Case Vignettes 91 that support. 1996 Casey DE. the patient had a friend who recently experienced acute renal failure due to some unrelated cause. his venlafaxine was decreased to 37. 2002 Bymaster FP. Psychopharmacology 166(4):391–399. Although the patient did not experience any typical serotonin withdrawal symptoms.

1996 Masood GR. However. venlafaxine and paroxetine. 2002 Liu BA. the offsetting exposures to both an SIADH-producing agent (venlafaxine) and an antidiuretic hormone antagonist (lithium) allowed him to tolerate his combined regimen without difficulty. et al: Lithium-induced reduction in urinary concentrating ability and urinary aquaporin 2 (AQP2) excretion in healthy volunteers. et al: Fanconi and inappropriate secretion of antidiuretic hormone syndromes secondary to venlafaxine therapy. Bedford JJ. In some individuals. et al: Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: a review of spontaneous reports. 2005 . for this patient. Weggery S. CMAJ 155:519–527. However. leading to the development of marked polyuria. Mittmann N. Kidney Int 67:291–294. 1997 Walker RJ. This patient’s history suggests that he was one of those unfortunate individuals who has an exceptional degree of increased urinary production when exposed to lithium. this effect can be quite troublesome. and this effect seems to result from increased serotonin neurotransmission (Liu et al. Venlafaxine is also a potent inhibitor of serotonin reuptake. and within 3 days the patient’s polyuria had almost completely resolved (N. 2002. 1997). Nephron 92:944–946. 1998 Meynaar IA. 1998. Karki SD. Peeters AJ. Patterson WR: Hyponatremia with venlafaxine. The psychiatrist therefore restarted the venlafaxine. 2005). it seems that he was fortunate that venlafaxine produced a counteracting effect that enabled him to tolerate lithium treatment. Launay-Vacher V. Discussion This is an example of offsetting drug side effects. Ann Pharmacotherapy 32:49–51. lithium’s propensity to increase urine production was no longer inhibited. 1996). Knowles SR. and there are case reports of venlafaxine producing SIADH (Izzedine et al. August 2006). Neth J Med 50:243–245. et al: Syndrome of inappropriate ADH secretion attributed to the serotonin re-uptake inhibitors. References Izzedine H. when the venlafaxine was discontinued.92 Drug–Drug Interaction Primer likely causative factor. producing frank diabetes insipidus. Sandson. Thus. Lithium is well known to produce some degree of increased urine production through antagonism of the action of antidiuretic hormone at the collecting tubule of the nephron (Walker et al. Mulder AH. personal communication. Masood et al. Ciroldi M. SIADH occasionally occurs in individuals (most often in the elderly) who take a selective serotonin reuptake inhibitor. namely a syndrome of inappropriate antidiuretic hormone production (SIADH). Meynaar et al.

With the cessation of smoking that accompanied admission to the hospital. and this was the most likely cause of his recent decompensation. 1998. Second. First. Discussion This is an example of reversal of induction. an increase in R-warfarin levels leads to more inhibition of the metabolism of S-warfarin. The less active R-warfarin isomer is metabolized primarily at 1A2 (Lehmann 2000). resulting in an increase in the blood level of R-warfarin. with which he had remained compliant. R-warfarin does produce some direct anticoagulant effect. The patient normally smoked two packs per day. This decrease in available 1A2 led to decreased metabolism of R-warfarin. patients were instead offered Nicotrol inhalers.Psychiatry Case Vignettes 93 THE LAW OF UNINTENDED CONSEQUENCES (II) A 55-year-old male with a history of bipolar I disorder presented involuntarily to a tertiary psychiatric hospital with a psychotic mania. 1987. The more active S-warfarin isomer is metabolized primarily by P450 2C9 (Heimark et al. 5 mg/day. the hospital became “smoke-free. he became acutely threatening toward a staff member. Thus. His international normalized ratio (INR) on admission was 2. is a significant 1A2 inducer (Schrenk et al. Since then.” Instead of smoke breaks. Linder and Valdes 1999). . Warfarin’s metabolism is very complex. No other signs of acute bleeding were found on physical examination. and the hospital staff needed to appropriately physically restrain him in the process of placing him in locked-door seclusion. although it is a less potent anticoagulant than Swarfarin. the patient’s available complement of 1A2 steadily decreased over the next several days. although there had been no change in the patient’s warfarin dosage. but he found that the Nicotrol inhaler satisfied his tobacco cravings. Tobacco use. He had been noncompliant with his lithium and aripiprazole (Abilify). nursing staff noted large bruises where staff had handled him. 1991). he had been maintained on warfarin (Coumadin). This increase in Rwarfarin led to an increase in the INR (Evans and Lewis 2005) through two main mechanisms. During one of his scheduled breaks.1. R-warfarin is itself an inhibitor of P450 2C9 (Kunze et al. Two years ago. A followup INR was found to be 4. the patient developed a deep venous thrombosis that produced a pulmonary embolus.7. One week into his admission. Zevin and Benowitz 1999). The hospitalist was called to evaluate the patient. yielding higher S-warfarin levels and a subsequent increase in INR. via cigarette smoking. Several months prior to his manic episode.

1987 Kunze KL. She was planning to reenter college on a limited basis. who was able to see her immediately. Eddy AC. October 2004).281 ng/mL (G. Eckermann. Benowitz NL: Drug interactions with tobacco smoking: an update. eventually titrating to a dosage of 400 mg/day (blood level. et al: Metabolic enantiomeric interactions: the inhibition of human (S)-warfarin-7-hydroxylase by (R)-warfarin. and dizziness. Lewis GM: Increase in international normalized ratio after smoking cessation in a patient receiving warfarin. 1991 Lehmann DE: Enzymatic shunting: resolving the acetaminophen-warfarin controversy.94 Drug–Drug Interaction Primer References Evans M. Her psychiatrist decided to initiate a trial of clozapine (Clozaril). Gibaldi M. Chirality 3:24–29. Her oral contraceptive was also discontinued.” with powers that exceeded even the president’s. Three days later. personal communication. et al: The mechanism of the warfarin–rifampin drug interaction. Pharmacotherapy 25:1656–1659. 2000 Linder MW. and she had started dating a young man she had met while working as a volunteer in the hospital gift shop. Clin Pharmacol Ther 42:388–394. 1999 Schrenk D. Gibaldi M. 2005 Heimark LD. . et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. and haloperidol (Haldol). Eur J Clin Pharmacol 53:361–367. 1999 THE TEKULEK A 27-year-old female with chronic undifferentiated schizophrenia presented as an involuntary admission to an inpatient psychiatric unit due to disruptive and unsafe behaviors. She was planting herself in the middle of busy intersections and proclaiming that she was the “Grand Tekulek. Mol Diagn 4:365–379. The psychiatrist determined that she was orthostatic and arranged for her to be evaluated in the emergency room. This relationship progressed to the point that she visited her internist in order to start taking an oral contraceptive. 1998 Zevin S. Trager WF. She had previously failed trials of risperidone (Risperdal). the patient enjoyed a remarkable recovery of her functioning. the patient was experienced marked drowsiness. she was feeling much better. Within 1 week of beginning the contraceptive. Over the next 6 months. She reported this sequence of events to her psychiatrist. and the laboratory reported that her clozapine level had increased to 1. 448 µg/mL). Valdes R Jr: Pharmacogenetics in the practice of laboratory medicine. Clin Pharmacokinet 36:425–438. olanzapine (Zyprexa). Brockmeier D. Pharmacotherapy 20:1464–1468. She was stabilized in the emergency room and blood was drawn for laboratory studies to determine the cause of her new symptoms. anergy. Morike K.

Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. He recognized the irrationality of this symptom and embarked on some . J Clin Pharmacol 41:823–832. J Clin Pharmacol 45:1413–1421. Clozapine’s metabolism occurs primarily at 1A2. The oral contraceptive that the patient started taking contained ethinylestradiol. 2005 Olesen OV. the patient experienced a resurgence of his old symptom of hoarding any and all possessions in his home. et al: Oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of tizanidine by inhibiting cytochrome P450 1A2. Victory J. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Johansson I. This decrease in the metabolism of clozapine led to a significant rise (almost triple) in the clozapine blood level. which is an inhibitor of both 1A2 and 2C19 (Granfors et al. orthostasis. even though the clozapine dosage had not been changed. with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. and they would talk frequently during smoke breaks. 2001 Shelepova T. Thus. the proximity to a new friend who was a frequent smoker led him to resume this habit. 1997. the addition of the ethinylestradiol impaired the ability of 1A2 and 2C19 to significantly contribute to the metabolism of clozapine. he increasingly found himself unable to bear the thought of parting with any item he might conceivably need in the future. Over the ensuing weeks. Clin Pharmacol Ther 78:400– 411. Br J Clin Pharmacol 44:439–446. 2005 HOARDER A 33-year-old mental health worker with obsessive-compulsive disorder had done well for the 5 years on fluvoxamine (Luvox). fast food refuse. Whether the items were old newspapers. Laitila J. 2005). He had befriended one of the newer mental health workers on his unit. Engel G. 300 mg/day. The enzymes 3A4 and 2C19 are also significant contributors. Although the patient had quit smoking more than 10 years earlier. Shelepova et al. or junk mail. and anergy. 1997 Granfors MT.Psychiatry Case Vignettes 95 Discussion This is an example of an inhibitor added to a substrate. This resulted in the patient’s sedation. Backman JT. Nafziger AN. Olesen and Linnet 2001). 2005. References Eiermann B. et al: Effect of triphasic oral contraceptive on drug-metabolizing enzyme activity as measured by the validated Cooperstown 5+1 cocktail.

Zevin and Benowitz 1999). et al: Effect of cigarette smoking on fluvoxamine pharmacokinetics in humans. 1995 Zevin S. 1999 OBSCENITIES A 19-year-old male diagnosed with Tourette’s disorder had managed his symptoms with haloperidol (Haldol). Several weeks later. Clin Pharmacol Ther 71:141–152. Brockmeier D. resulting in a decrease in the blood level of fluvoxamine (Spigset et al. During his freshman year at college. Weeks later. When the patient resumed smoking. his hoarding remitted. slowing the metabolism of fluvoxamine and thus allowing fluvoxamine levels to reachieve their higher. Clin Pharmacol Ther 58:399–403. Mihara K. Morike K. Eur J Clin Pharmacol 53:361–367. is a significant 1A2 inducer (Schrenk et al. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. Clin Pharmacokinet 36:425–438. 2002). Discussion This is an example of an inducer added to a substrate. but this was not successful. This led to a resurgence of obsessive-compulsive symptoms. This led the psychiatrist and the patient to do some research. and over the next few weeks. Following cessation of smoking. he significantly increased the amount of 1A2 that was available to metabolize the fluvoxamine. therapeutically effective baseline. it also emerged that he had resumed smoking. Hedenmalm K. References Christensen M. 2002 Schrenk D. when he related this symptom recurrence to his psychiatrist. Tobacco use. 1998 Spigset O. the amount of available 1A2 returned to its lower baseline. 1995) even though the dosage had not been decreased. which revealed the need to either increase the fluvoxamine dosage past the package insert recommended maximum or to discontinue smoking. The patient opted for the latter. Carleborg L. 1998. Fluvoxamine is a substrate of both 1A2 and 2D6 (Christensen et al. he unex- . he picked up the habit of smoking and quickly progressed to one pack per day. during a stressful examination. via cigarette smoking.96 Drug–Drug Interaction Primer “booster” sessions of cognitive-behavioral therapy with his therapist. 5 mg/day. Tybring G. Benowitz NL: Drug interactions with tobacco smoking: an update.

2D6. endorsing . he was able to explain to him why his symptoms had returned. 1998 Shimoda K. Morita S. Clin Pharmacokinet 36:425–438. He had not tolerated previous trials of lithium and valproate. He managed to largely suppress this during the examination. had been stably maintained on carbamazepine (Tegretol). 2001. et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. Due to his anxiety. Zevin and Benowitz 1999). 1999) even though the dosage had not been decreased. a problem he had not encountered for several years. Discussion This is an example of an inducer added to a substrate. and phase II glucuronidation (Desai et al. he was smoking in the waiting room when his psychiatrist came out of his office to invite him inside. 10. Ishizaki T: Pharmacokinetics of haloperidol: an update. 1999 THE ROAD TO HELL IS PAVED WITH INDICATIONS A 37-year-old male with bipolar I disorder. When the patient began smoking. Jann MW: Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. Morike K. He immediately made an appointment with his psychiatrist. Ther Drug Monit 21:293–296. resulting in a decrease in the blood level of haloperidol (Shimoda et al. 1A2. This led to a resurgence of verbal tics. Kudo and Ishizaki 1999). he became acutely depressed. Eur J Clin Pharmacol 53:361–367. The psychiatrist thus learned that the patient had begun smoking. via cigarette smoking. he significantly increased the amount of 1A2 that was available to metabolize the haloperidol. et al: Lower plasma levels of haloperidol in smoking than in nonsmoking schizophrenic patients. 1999 Schrenk D. 800 mg/day (blood level. Benowitz NL: Drug interactions with tobacco smoking: an update. 1999 Zevin S. Tobacco use. After the death of his sister. Brockmeier D. Seabolt J. and when he learned the reason for this urgent appointment. Someya T. 2001 Kudo S. References Desai HD. 1998.Psychiatry Case Vignettes 97 pectedly found himself voicing a few obscenities. Clin Pharmacokinet 37:435–456. is a significant 1A2 inducer (Schrenk et al. Haloperidol is metabolized by 3A4. whose illness course had been characterized by infrequent manic episodes and even fewer depressions. CNS Drugs 15:469–494.8 µg/mL).

In addition to inhibiting 3A4. he directed his patient to that hospital’s laboratory for a carbamazepine level. 1A2. 1996a. Curr Drug Metab 3:13–37. 2004). 2E1.98 Drug–Drug Interaction Primer dysphoria. Carbamazepine is a substrate of the P-glycoprotein transporter (Potschka et al. 2003). 1991 Hemeryck A. Spina et al. Jann MW. Carbamazepine is primarily a 3A4 substrate. the patient did not display clinical improvement. Belpaire FM: Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug–drug interactions: an update. the blood level of carbamazepine rose even though the carbamazepine dosage had not been increased (Grimsley et al. Over the next 2 weeks. 2002 . References Grimsley SR. but he did develop new-onset sedation. Clin Pharmacol Ther 50:10–15. thus increasing net absorption and decreasing net excretion of carbamazepine. It is also likely that alterations in the functioning of the P-glycoprotein transporter contributed to this interaction. 1991). which had risen to 16. Sayal et al. fluoxetine also raised carbamazepine levels by impairing the ability of P-glycoprotein to extrude carbamazepine from enterocytes back into the gut lumen. hypersomnia. and passive death wishes. and fluoxetine (Symbyax 6/25). 2B6. anhedonia. He denied any psychotic symptoms. Consequently. 1996. 2C9. where it would then be excreted rather than absorbed. decreased appetite. and 2C9. these symptoms did not begin to develop until several days after Symbyax was started. Curiously. The addition of fluoxetine (one of the components of Symbyax) led to a significant impairment in the ability of 3A4. 25 mg/day. with 1A2. His psychiatrist opted to initiate a trial of combined olanzapine. 2001). 6 mg/day. tremulousness. anergy. 2002. and fluoxetine is an inhibitor of this transporter (Weiss et al. and phase II enzymes (uridine 5′-diphosphate glucuronosyltransferase 2B7) making minor contributions to carbamazepine’s metabolism (Pearce et al. et al: Increased carbamazepine plasma concentrations after fluoxetine coadministration. 1996b). 1A2.9 µg/mL.S. Carter JG. and 3A4 (Hemeryck and Belpaire 2002. After consulting with a pharmacist at an affiliated hospital. Discussion This is an example of an inhibitor added to a substrate. Staines et al. von Moltke et al. 2C8/9. and 2C9 to efficiently metabolize the carbamazepine. 2000. and nausea. Fluoxetine and its active norfluoxetine metabolite together mildly to moderately inhibit 1A2. because this was the only compound that had receives a U. Food and Drug Administration indication for the treatment of bipolar depression.

family obligations). SPEAK NO EVIL A 25-year-old male medical student had been taking carbamazepine (Tegretol).3 µg/mL) as a successful treatment for a complex partial seizure disorder. Greenblatt DJ. detail-oriented style that had worked well for the first 2 years was now leading evaluating residents and attending physicians to cite his “inefficiency” and “difficulty prioritizing clinical tasks. Vakkalagadda GR. J Pharmacol Exp Ther 305:197–204. 1. J Pharmacol Exp Ther 311:1131–1137. HEAR NO EVIL. His obsessional. friendships.and 3-hydroxylated metabolites. Duncan-McConnell DA. leading him to further compromise already neglected aspects of his outside life (e. 2003 SEE NO EVIL. Fedrowitz M. McConnell HW. Acta Psychiatr Scand 102:250–255. rapidly titrated to 200 mg/day. Duan SX. In the middle of his third year of medical school.. had responded well to fluvoxamine. et al: Inhibition of P-glycoprotein by newer antidepressants. 1996 Staines AG. 9. health. 2002 Potschka H. Clin Pharmacokinet 31:198–214. 1996b Weiss J. He began to experience dysphoria. and weight loss. Harmatz JS. Burchell B: N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. the patient noted increasing leth- . 2001 Sayal KS. et al: Psychotropic interactions with warfarin. His older brother. Coughtrie MW. Pisani F. Martin-Facklam M. Drug Metab Dispos 30:1170–1179. 2004 von Moltke LL. The patient made an appointment with his internist. decreased concentration and energy.g. nefazodone and venlafaxine. who had encountered similar issues and difficulties. SSRI antidepressants. Neuroreport 12:3557–3560. 1996a von Moltke LL. 2000 Spina E. Leeder JS: Pathways of carbamazepine bioactivation in vitro. he was having difficulty translating his success in the basic sciences to his clinical work. who started him on fluvoxamine (Luvox). poor sleep. J Pharmacol Exp Ther 276:370–379. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Loscher W: P-glycoprotein and multidrug resistance– associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. et al: Phenacetin O-deethylation by human liver microsomes in vitro: inhibition by chemical probes.” His perfectionism drove him to spend even more time at work. Over the next several days.000 mg/day (blood level. et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole.Psychiatry Case Vignettes 99 Pearce RE. Psychopharmacology (Berl) 128:398–407. Greenblatt DJ. I: characterization of human cytochromes P450 responsible for the formation of 2. Dormann SM.

he did not hear his alarm and overslept by 4 hours. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Consequently. 2002. 2001) and fluvoxamine is an inhibitor of this transporter (Weiss et al. Carbamazepine is primarily a 3A4 substrate. 2002 . 2C8/9. References Christensen M. 1991). 2B6. Discussion This is an example of an inhibitor added to a substrate. 2004). 1A2. and 2C9. Clin Pharmacol Ther 71:141–152.100 Drug–Drug Interaction Primer argy and occasional nausea. In addition to inhibiting 3A4. thus increasing net absorption and decreasing net excretion of carbamazepine. where his carbamazepine level had risen to 18.4 µg/mL. 1996. Acta Psychiatr Scand 84:583–584. Staines et al. Carbamazepine is a substrate of the P-glycoprotein transporter (Potschka et al. The addition of fluvoxamine led to a significant impairment in the ability of 3A4. Hemeryck and Belpaire 2002. His speech was slurred and he felt “drugged. Sayal et al.” He contacted his internist. Fluvoxamine is a potent inhibitor of 1A2 and a mild to moderate inhibitor of 3A4 and 2C9 (Christensen et al. 1995 Fritze J. 1A2. Thevenon-Gignac C. Regnaut N. 2002. Consequences for the carbamazepine plasma level]. His vision had become so blurry he was having difficulty reading. Spina et al. Tybring G. Lanczik M: Interaction between carbamazepine and fluvoxamine. with 1A2. Unsorg B. 2E1. Fritze et al. fluvoxamine also raised carbamazepine levels by impairing the ability of P-glycoprotein to extrude carbamazepine from enterocytes back into the gut lumen. Encephale 21:141–145. 2003). 2002 Cottencin O. Belpaire FM: Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab 3:13–37. It is also likely that alterations in the functioning of the P-glycoprotein transporter contributed to this interaction. and 2C9 to efficiently metabolize the carbamazepine. 2000). Mihara K. et al: [Carbamazepine-fluvoxamine interaction. where it would then be excreted rather than absorbed. the blood level of carbamazepine rose even though the carbamazepine dosage had not been increased (Cottencin et al. and phase II enzymes (uridine 5′-diphosphate glucuronosyltransferase 2B7) making minor contributions to carbamazepine’s metabolism (Pearce et al. who instructed him to report to the hospital emergency room. 1991 Hemeryck A. 1995. One week after starting the fluvoxamine.

He decided that because the patient did not have an underlying seizure disorder. Burchell B: N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. Neuroreport 12:3557–3560. who considered the possibility of a drug interaction. he did not require ongoing phenytoin. McConnell HW. 2001 Sayal KS. 60 mg/day. Timmer et al. Dormann SM. The patient recovered uneventfully from this episode and left the hospital taking both the mirtazapine and the phenytoin. whereupon he was sent to the nearest emergency room and admitted medically. 1996 Staines AG.4 µg/mL). Discussion This is an example of an inducer added to a substrate. even though he had remained abstinent from alcohol and seemed to be doing well psychosocially after this hospitalization. 2000. 2004 Weiss J. he had a generalized. Coughtrie MW. 2002 Potschka H. When . He met with his psychiatrist. et al: Psychotropic interactions with warfarin. Characterization of human cytochromes P450 responsible for the formation of 2. One month after tapering and discontinuing the patient’s phenytoin. Raucy 2003). Pisani F.and 3-hydroxylated metabolites. 300 mg/day (blood level. and bupropion. While withdrawing from an extended drinking binge. Roughly 2 months later. 2D6. he regained his usual level of antidepressant response. The hospitalist placed the patient on phenytoin (Dilantin). Fedrowitz M. Phenytoin is an inducer of multiple P450 enzymes. 2002. and 3A4 (Stormer et al. et al: Inhibition of P-glycoprotein by newer antidepressants.Psychiatry Case Vignettes 101 Pearce RE. Vakkalagadda GR. He had failed trials with three different selective serotonin reuptake inhibitors. Clin Pharmacokinet 31:198–214. Mirtazapine is a substrate of P450 1A2. J Pharmacol Exp Ther 311:1131–1137. Loscher W: P-glycoprotein and multidrug resistance– associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. 2000 Spina E. Acta Psychiatr Scand 102:250–255. tonic-clonic seizure. Duncan-McConnell DA. Martin-Facklam M. J Pharmacol Exp Ther 305:197–204. specifically including 3A4 (Gibson et al. 12. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. 2003 MISGUIDED MEASURES A 47-year-old male dually diagnosed with alcohol dependence and recurrent major depression had maintained a partial response with mirtazapine. Leeder JS: Pathways of carbamazepine bioactivation in vitro I. venlafaxine. 2000). Drug Metab Dispos 30:1170–1179. his depressive symptoms began to worsen.

2000 COMORBIDITIES A 43-year-old male with comorbid bipolar I disorder and obsessive-compulsive disorder (OCD) has been stably maintained for the past two years on a regimen of lithium (Lithobid). 2002 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Acute administration of benzodiazepines for acute prophylaxis of delirium tremens is the preferred manner of dealing with alcohol withdrawal seizures. Although there is debate about the utility of phenytoin if an alcohol withdrawal–induced seizure actually occurs. he experienced a nonpsychotic manic episode leading to a voluntary hospital admission. The patient was very resistant to trying any antipsychotic agents. 0. 600 mg bid (blood level. This drug interaction was particularly avoidable because phenytoin is not a desirable adjunct in the treatment of seizures that occur only in the context of alcohol withdrawal. van den Heuvel MW. 2000 Timmer CJ. Schnabel PG. After getting only 2 hours of sleep for two nights in a row to complete a work project. then phenytoin should be tapered and discontinued after acute alcohol withdrawal has subsided. References Gibson GG. One study indicates that on average. Drug Metab Dispos 31:533–539. the addition of phenytoin results in a 46% decrease in mirtazapine blood levels (Spaans et al. Toxicology 181–182:199–202. et al: Concomitant use of mirtazapine and phenytoin: a drug-drug interaction study in healthy male subjects. and 3A4. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. resulting in a decrease in the blood level of mirtazapine and loss of antidepressant efficacy. von Moltke LL. His psychiatrist opted to add carbamazepine (Tegretol). but he was rapidly becoming more preoccupied by cleanliness ob- . 2D6. Clin Pharmacokinet 38:461–474. 2003 Spaans E. Delbressine LP: Clinical pharmacokinetics of mirtazapine. 2002). titrating to 1. Eur J Clin Pharmacol 58:423–429. Drug Metab Dispos 28:1168–1175. et al: Metabolism of the antidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2.1 µg/mL). Within 2 weeks. Sitsen JM.000 mg/day (blood level. 2002 Stormer E. this led to a significant increase in the amount of 3A4 that was available to metabolize the mirtazapine. 200 mg/day. if it is used. Shader RI. el-Sankary W. 10.102 Drug–Drug Interaction Primer phenytoin was added to the regimen.9 mEq/mL) and sertraline (Zoloft). Previous attempts to decrease his sertraline had resulted in a recurrence of OCD symptoms. even though the dosage had not been decreased. the patient’s mania did respond favorably.

Molloy M. Eliasson E: Significant reduction of sertraline plasma levels by carbamazepine and phenytoin. Discussion This is an example of an inducer added to a substrate. 2D6. his carbamazepine was then tapered and discontinued. After 2 weeks on this dosage of risperidone. Eur J Clin Pharmacol 57:915–916. References Arana GW. Ucar et al. et al: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Ishizuka T. An update. After consulting the hospital pharmacist and discussing options with the patient. even though the dosage had not been decreased (Pihlsgard and Eliasson 2002). However. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine. Increasing the dosage of sertraline would have been a perfectly reasonable approach to restore a remission of OCD symptoms. specifically including 2B6. 1996 . Over the following 3 weeks. Shimada N. Drug Metab Dispos 27:763–766. 2C9. resulting in a decrease in the blood level of sertraline and loss of efficacy in treating the patient’s OCD. Food and Drug Administration’s recommended maximum dosage of 200 mg/day that the psychiatrist and patient were more comfortable with a crossover from carbamazepine to risperidone. 1988. 2C9. Pisani F. 2004 Kobayashi K. and 3A4 (Arana et al. 2004). Faucette et al. 1988 Faucette SR. Sertraline is a substrate of P450 2B6. 2C9. Drug Metab Dispos 32:348–358. which was titrated to a dosage of 4 mg/day. 2002 Spina E. Spina et al. Miners and Birkett 1998. Carbamazepine is an inducer of multiple P450 enzymes. 2C19. 1999). Hamilton GA.Psychiatry Case Vignettes 103 sessions and cleaning rituals. Br J Clin Pharmacol 45:525–538. 1996. 2004. and 3A4 that were available to metabolize the sertraline. et al: Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. his OCD symptoms diminished greatly and he remained close to euthymic. this led to a significant increase in the amount of 2B6. which worked fine in this case. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. When carbamazepine was added to the sertraline. Birkett DJ: Cytochrome P4502C9: an enzyme of major importance in human drug metabolism.S. Clin Pharmacokinet 31:198–214. J Clin Psychiatry 49:448– 449. 1999 Miners JO. the patient eventually agreed to a trial with risperidone. and 3A4 (Kobayashi et al. this would have involved giving a sertraline dose so far above the U. Wang H. 1998 Pihlsgard M. Epstein S.

800 mg/day (blood level. this led to a significant increase in the amount of 2C9. 1997. 3A4. Olesen and Linnet 2001). the decision was made to keep the patient on clozapine. Clozapine’s metabolism occurs primarily at 1A2. and UGT1A4 (Bottiger et al. specifically including 2C9. A negative work-up suggested that the cause for these seizures was the clozapine. 400 mg/day (blood level. Phenytoin is an inducer of multiple enzymes. 2C9. The enzymes 3A4 and 2C19 are also significant contributors. 1998. this dosage produced a blood level of 458 ng/mL. Another clozapine level drawn 5 days after hospitalization. and uridine 5′diphosphate glucuronosyltransferase (UGT) 1A3 and 1A4 playing only minor metabolic roles (Breyer-Pfaff and Wachsmuth 2001. 2004 A PLETHORA OF PILLS A 37-year-old male with schizophrenia had failed trials of haloperidol. after 6 months at this dosage.000 mg/day. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. 2C19. 15. Gibson et al. Within 1 month. as well as seeming more distracted. When phenytoin was added to the clozapine. It is estimated that adding phenytoin to clozapine results in a roughly 65%–85% . 2002. Chetty et al. Eur J Clin Pharmacol 59:879– 882. 3A4. and aripiprazole before finally responding to clozapine. the patient’s seizures had completely remitted. 2C19. was added to his regimen. and UGT1A4 that were available to metabolize the clozapine. the psychiatrist titrated the patient’s clozapine to a dose of 3. His clozapine level at that time had fallen to 119 ng/mL. the patient again became preoccupied with looking at himself in the mirror for many hours each day. Neuvonen M. When he started stealing and destroying the underwear of his roommates in his group home. and withdrawn. Unfortunately. Raucy 2003). olanzapine.104 Drug–Drug Interaction Primer Ucar M. when compliance could be assured. the patient developed new-onset seizures. and the patient symptoms greatly decreased over the ensuing month. However. but because no other antipsychotic agents had proven helpful. was still only 127 ng/mL. However. 500 ng/mL). Eiermann et al. with 2D6. guarded. 1999. Discussion This is an example of an inducer added to a substrate. Luurila H. After consulting with the hospital pharmacist. a neurologist was consulted and phenytoin (Dilantin). quetiapine. resulting in a decrease in the blood level of clozapine and loss of antipsychotic efficacy even though the dosage had not been decreased. At steady state. this confirmed that he had decompensated to his pre-clozapine baseline. and he was rehospitalized.8 µg/mL).

1997 Gibson GG. nausea. One area that she decided to change was her habit of drinking two sodas each day. 2005). Miller R. Drug Metab Dispos 29:1343–1348. J Clin Pharmacol 41:823–832. Svensson JO. 1997). When she visited her internist for a check-up. She decided that she would instead consume grapefruit juice in place of the sodas. 2001 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Buspirone is a substrate of P450 3A4 (Kivisto et al. 1998). Armstrong SC. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. she experienced rapid and new-onset headache. Stahle L: Lamotrigine drug interactions in a TDM material. el-Sankary W. 2003 GRAPEFRUIT GAFFE A 45-year-old female with generalized anxiety disorder had responded well for several years to buspirone (Buspar). thus it has been suggested that one can compensate for this by multiplying clozapine doses by a factor of four after phenytoin has been added (deLeon et al. the internist praised her efforts but advised her to find a different “healthy” beverage. Toxicology 181–182:199–202. 2002 Miller DD: Effect of phenytoin on plasma clozapine concentrations in two patients. Johansson I. Ther Drug Monit 20:60–62. Ther Drug Monit 21:171–174. 1991 Olesen OV.Psychiatry Case Vignettes 105 decrease in blood levels (Miller 1991). Seymour MA: Phenytoin auto-induction. J Clin Psychiatry 52:23–25. Thus the addition of . Br J Clin Pharmacol 44:439–446. References Bottiger Y. 2001 Chetty M. Cozza KL: The dosing of atypical antipsychotics. within the next 2 days. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. he advised her to lose some weight and eat more healthfully. Grapefruit juice is an inhibitor of intestinal 3A4 (He et al. Wachsmuth H: Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine. 2005 Eiermann B. However. Drug Metab Dispos 31:533–539. After some quick research. She contacted her internist and described her symptoms and her recent decision to start drinking grapefruit juice. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. Discussion This is an example of an inhibitor added to a substrate. and dizziness. 20 mg bid. 1998 deLeon J. Psychosomatics 46:262–273. Engel G. 1999 Breyer-Pfaff U.

Hayes RN. There is also a table detailing DDIs involving a few psychotropics not included in these three broad classes as well as select nonpsychotropic agents (e. a more than fourfold increase in peak levels of buspirone (Lilja et al. 1997 Lilja JJ. One study demonstrated that the addition of grapefruit juice to buspirone produced. even though the dosage had not been increased. Kivisto KT. 1998 NOTE For a thorough review of drug–drug interactions (DDIs) involving psychotropic agents.. tobacco. consult Appendix A. Iyer KR.g. In this case. and mood stabilizing agents as well as tables that detail all known and clinically significant DDIs between pairings of any two agents from these drug classes. 1998 Kivisto KT.106 Drug–Drug Interaction Primer grapefruit juice impaired the ability of intestinal 3A4 to significantly contribute to the metabolism of buspirone. References He K. It contains the metabolic pathways and inhibitory and inductive profiles for antidepressants. Clin Pharmacol Ther 62:348–354. et al: Grapefruit juice substantially increases plasma concentrations of buspirone. on average. Kantola T. antipsychotics. Backman JT. 1998). statins). et al: Inactivation of cytochrome P450 3A4 by bergamottin. Clin Pharmacol Ther 64:655–660. et al: Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole. This led to an increase in the blood level of buspirone. Lamberg TS. a component of grapefruit juice. that was sufficient to generate these new side effects from a significantly increased concentration of buspirone. Chem Res Toxicol 11:252–259. . This appendix is a reprint of an article that appeared in the journal Psychosomatics in 2005. ethinylestradiol.

One week after reaching this dosage. his symptoms fully remitted.Chapter 3 INTERNAL MEDICINE CASE VIGNETTES THE CURE CAN BE WORSE THAN THE DISEASE A 35-year-old man with a history of recurrent melancholic major depressive disorder had been stably maintained for over 3 years on a regimen of desipramine (Norpramin). with a stable blood level of around 150 ng/mL. 107 . the patient began to experience frequent palpitations and accompanying light-headedness. who evaluated the patient. 200 mg/day. The patient’s electrocardiogram showed a sinus tachycardia of 132 beats per minute and QRS interval widening to a duration of 160 msec. His father had died in his mid-40s from a myocardial infarction. A week after the desipramine was stopped. and the result was 623 ng/mL. As part of this program. the physician started the patient on bupropion (Zyban. The patient was admitted to a telemetry unit. where a desipramine level was drawn before the drug was discontinued. Accordingly. in this application). titrating to a dosage of 150 mg bid. this patient’s family physician strongly advised the patient to participate in an aggressive smoking cessation program. He reported these symptoms to his family physician. The patient was also a two-pack-per-day smoker.

back pain.108 Drug–Drug Interaction Primer Discussion This is an example of an inhibitor added to a substrate. At this dosage. even though the desipramine dosage had not been changed. Her bloating led to increasing nausea and even vomiting. Her increasing inability to tolerate oral intake led her to visit the local emergency room. et al: Inhibition of CYP2D6 activity by bupropion. References Dahl ML. finally succumbed to old age and passed away. GlaxoSmithKline. Alm C. 1993 GlaxoSmithKline: Wellbutrin (package insert). Research Triangle Park. 2005 BLOATED A 37-year-old woman with a long-standing history of panic disorder had been experiencing only one panic attack per month for the past several years while taking amitriptyline (Elavil). the patient began to experience abdominal cramping. Desipramine. 175 mg/day. her panic attacks increased in frequency (to five times per week) and intensity. the addition of bupropion (albeit in the form of Zyban) impaired the ability of 2D6 to efficiently metabolize the desipramine. capable of elevating desipramine blood levels to two to five times baseline (GlaxoSmithKline 2001. Brauer LH. Kotlyar et al. Tracy TS. 2001 Kotlyar M. and a pervasive feeling of being bloated. However. At the same time the psychiatrist also added paroxetine (Paxil). Ten days after starting the paroxetine. Eur J Clin Pharmacol 44:445–450. to her regimen. The resultant cardiac toxicity (via excessive quinidine-like effects of toxic tricyclic levels) led to the symptoms of palpitations and dizziness. Bupropion is a relatively potent 2D6 inhibitor. Her . where a gastrointestinal workup revealed a partial small bowel obstruction due to an adynamic ileus. which led to a more than fourfold increase in the desipramine blood level in this case. 0. et al: Polymorphic 2-hydroxylation of desipramine: a population and family study. her psychiatrist added clonazepam (Klonopin). is metabolized primarily at 2D6 (Dahl et al. who had helped provide a sense of companionship and security. She was admitted to the hospital. She had a significant decrease in her frequency of bowel movements. Following the loss of this cherished pet. NC.5 mg tid. J Clin Psychopharmacol 25:226–229. 2005). her blood level of amitriptyline + nortriptyline ranged from 150 to 180 ng/mL. 1993). Thus. In an effort to address this. her pet Labrador. 10 mg/day for 4 days and 20 mg/day thereafter while simultaneously decreasing the amitriptyline to 150 mg/day. as a secondary-amine tricyclic antidepressant. Iselius L.

and 2D6. J Clin Psychopharmacol 15:125–131. Ruths. 2D6 catalyzes hydroxylation of both amitriptyline and nortriptyline (Venkatakrishnan et al. 1999). 100 mg/day (most recent blood level. 1998. which led to a three. 91 ng/mL). von Moltke LL. whereupon he discovered that he was HIV positive. 1995). A new girlfriend insisted on his obtaining an HIV test before they began to have sexual relations. 3A4. Discussion This is an example of an inhibitor added to a substrate. bloating. Paroxetine is a strong competitive inhibitor of 2D6 (von Moltke et al. Greenblatt DJ: Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs. June 2002). Amitriptyline is a tertiary-amine tricyclic antidepressant whose metabolism depends most on the intact functioning of 2C19. It also led to the quinidine-like changes in cardiac conduction that were observed after she was placed on a heart monitor. Court MH. The resultant state of tricyclic toxicity led to the patient’s adynamic ileus and associated cramping. whereupon she was also placed on a heart monitor (S. Nortriptyline is amitriptyline’s primary metabolite via demethylation by 2C19 and 3A4. Greenblatt DJ.Internal Medicine Case Vignettes 109 amitriptyline + nortriptyline blood level was found to be 694 ng/mL. vomiting. 1995 WINDOW A 42-year-old man with recurrent major depression and a remote history of intravenous drug abuse was being stably maintained on nortriptyline (Pamelor). et al: Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4. Greenblatt DJ.to fourfold increase in the amitriptyline + nortriptyline blood level despite a modest decrease in amitriptyline dosage (from 175 mg/day to 150 mg/day). References Venkatakrishnan K. After verifying . Thus. personal communication. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Pharmacol 39:567–577. von Moltke LL. and back pain. 1999 von Moltke LL. with 1A2 serving as a secondary enzyme. J Clin Pharmacol 38:112–121. the addition of paroxetine significantly impaired the ability of 2D6 to contribute to the metabolism of amitriptyline and nortriptyline. 1998 Venkatakrishnan K.

MD. decreased antidepressant efficacy when nortriptyline blood levels are greater than 150 ng/mL is thought to be unrelated to the presence of any tricyclic antidepressant toxicity state. 1998 Llibre J. insomnia. 2001 . and another blood level 1 week later was 112 ng/mL. his internist prescribed ritonavir (Norvir). Williams and Wilkins. Studies have suggested that nortriptyline demonstrates a therapeutic blood level window of 50–150 ng/mL. which he found had risen to 218 ng/mL. Discussion This is an example of an inhibitor added to a substrate. 1998). Baltimore. the patient experienced increasing irritability. the depressive symptoms had remitted (K. and 3A4) (Greenblatt et al. von Moltke et al. leading to the emergence of depressive symptoms. Clin Pharmacol Ther 67:335–341.) A reduction in the nortriptyline dosage to 50 mg/day compensated for ritonavir’s 2D6 inhibition. thus yielding a higher blood level of nortriptyline even though the dosage had not been increased. (Incidentally. and demoralization. 2000. Over the next 2 weeks. After another week. et al: Severe interaction between ritonavir and acenocoumarol. 2C9. Fearing that a drug interaction had occurred. and ritonavir is a 2D6 inhibitor (as well as an inhibitor of most P450 enzymes except 1A2. Ohtani H: Pharmacokinetics and drug interactions of antidepressive agents (in Japanese). May 2002). the increase in the patient’s nortriptyline level from 91 ng/mL to 218 ng/mL caused by ritonavir’s 2D6 inhibition represented a departure from this therapeutic window. 8th Edition. Nippon Rinsho 59:1539–1545. 2C19. The internist decreased the nortriptyline dosage to 50 mg/day. Cozza. Sadock B: Kaplan and Sadock’s Synopsis of Psychiatry. such that levels below 50 ng/mL and levels above 150 ng/mL tend to be less effective in treating depressive symptoms (Kaplan and Sadock 1998). leading to a final nortriptyline blood level that was within the therapeutic window and resolution of the patient’s depressive symptoms. personal communication. Lopez E. von Moltke LL. Romeu J. References Greenblatt DJ. 2002. 2002 Sawada Y. Nortriptyline is a 2D6 substrate (Sawada and Ohtani 2001). 2000 Kaplan H. Hence. dysphoria.110 Drug–Drug Interaction Primer that this result was not a false positive. Llibre et al. Behavioral Sciences/Clinical Psychiatry.L. and a later inducer of 1A2. The addition of the ritonavir impaired the ability of 2D6 to efficiently metabolize the nortriptyline. et al: Alprazolam-ritonavir interaction: implications for product labeling. the internist ordered a nortriptyline blood level. Harmatz JS. Ann Pharmacother 36:621–623.

However. July 2002). and she enjoyed both antidepressant efficacy and a lowering of her cholesterol level (to 210 mg/dL) (S. who advised placing the patient on citalopram (Celexa) and pravastatin (Pravachol) after allowing some weeks for these symptoms to abate. her internist tried to add simvastatin (Zocor) to her regimen and titrated this medication to a dosage of 80 mg/day. and her creatine phosphokinase level was also at the upper end of the normal range. and its active metabolite. which was started at 10 mg/day initially and titrated to a dosage of 30 mg/day. Discussion This is an example of substrates added to an inhibitor. she again experienced extreme fatigue and mild confusion. Neuvonen et al. 40 mg/day. von Moltke et al. which was well controlled with fluoxetine (Prozac). Fluoxetine is a strong 2D6 inhibitor. Her internist prescribed atorvastatin (Lipitor). Routine blood monitoring had unearthed a cholesterol level of 275 mg/dL. Blood tests revealed similar elevations of her LFTs. when atorvastatin and simvastatin were added to the fluoxetine. and a mild confusional state. The atorvastatin was discontinued. the patient gradually developed extreme fatigue. is a moderate 3A4 inhibitor (Greenblatt et al. alanine transaminase. 1998 STYMIED BY STATINS (I) A 50-year-old woman had a long-standing history of atypical depression. Atorvastatin and simvastatin are 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors that are primarily metabolized by 3A4 (Gruer et al. her cholesterol was still 255 mg/dL. The fluoxetine was continued throughout. so the dosage of atorvastatin was further raised to 50 mg/day. and γ-glutamyltransferase)—although these were still within the upper limits of the reported normal range. Strahan. Greenblatt DJ. J Clin Pharmacol 38:106–111. whereas pravastatin relies on more heterogeneous hepatic metabolism as well as significant renal excretion (Hatanaka 2000). The internist stopped both the simvastatin and the fluoxetine and called his P450-savvy psychiatrist friend.Internal Medicine Case Vignettes 111 von Moltke LL. 1995). generalized pruritis. 1999. and the symptoms gradually resolved over the next 2 weeks. After 1 month at this dosage. Within the next 2 weeks. Stevens and Wrighton 1993. Lennernas 2003. their me- . along with a doubling of her liver function tests (LFTs)—aspartate transaminase. The patient tolerated this combination without difficulty. Grassi JM. 1998). and dietary interventions had thus far proven ineffective in correcting this. personal communication. Two months later. 1999. norfluoxetine. Thus. et al: Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir.

Mercuri MF. she visited her internist. for 10 days. et al: Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. when pravastatin (whose metabolism is difficult to inhibit) was combined with citalopram (which does not meaningfully inhibit 3A4) (Brosen and Naranjo 2001). Cozza. 1999 Hatanaka T: Clinical pharmacokinetics of pravastatin: mechanisms of pharmacokinetic events. When she developed a fever of 101. mild rhabdomyolysis). Court MH. et al: Human cytochromes and some newer antidepressants: kinetics. Clin Pharmacokinet 42:1141– 1160. Naranjo CA: Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. However. 4 mg/day. by her dermatologist for treatment of delusional parasitosis. Kivisto KT: Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Greenblatt DJ. who prescribed clarithromycin (Biaxin). Am J Cardiol 84:811–815. . One winter. Clin Pharmacol Ther 63:332–341. she caught the flu and began to cough frequently and painfully.112 Drug–Drug Interaction Primer tabolism at 3A4 was inhibited. J Clin Psychopharmacol 19(suppl):23S–35S. 500 mg bid. 2000 Lennernas H: Clinical pharmacokinetics of atorvastatin. and their resultant blood levels were greater than would have been expected in this patient at the dosages prescribed. Vega JM. mild delirium. personal communication. a tolerable and effective regimen was achieved. symptoms of HMG-CoA reductase inhibitor toxicity emerged (elevated LFTs. 1999 Gruer PJ. Kantola T. 1993 von Moltke LL. Harmatz JS. Eur Neuropsychopharmacol 11:275–283. Thus. References Brosen K. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. The patient had responded well to this dosage. 1995 A FATAL CASE OF BRONCHITIS A 55-year-old woman had been prescribed pimozide (Orap). J Clin Psychopharmacol 15:125–131. The postmortem examination led to a diagnosis of a fatal arrhythmia (K. 1998 Stevens JC. May 2002). and drug interactions.3°F. On day 5. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. Clin Pharmacokinet 39:397–412. von Moltke LL. 2001 Greenblatt DJ. metabolism. the patient went to sleep and never woke up. 2003 Neuvonen PJ. which she tolerated with only mild complaints of stiffness.L. J Pharmacol Exp Ther 266:964–971.

This caused the blood level of pimozide to increase significantly. 1998). dyspnea. Clarithromycin can also increase the QTc interval. even though the dosage of pimozide had not been changed. His cyclosporine blood level was far below the minimum effective value (Ruschitzka et al. the QTc interval likely increased significantly as well. He decided to obtain his own supply of St. and orthopnea as well as intermittent fevers. Pimozide can increase the QTc interval in a dose-dependent manner. References Desta Z. and clarithromycin is a strong competitive inhibitor of 3A4 (Desta et al. where he was found to be in congestive heart failure with an ejection fraction of 20%. et al: Identification and characterization of human cytochrome P450 isoforms interaction with pimozide. 2000). poor energy) in the weeks following this procedure. Roughly 1 month later.Internal Medicine Case Vignettes 113 Discussion This is an example of an inhibitor added to a substrate. Soukhova N. 1999). Because he was taking so many “artificial” drugs. The result was that the patient likely experienced a large QTc prolongation. 1999 NATURAL DISASTER (I) A 35-year-old man had just undergone a successful cardiac transplantation procedure to treat his debilitating cardiomyopathy. The addition of the clarithromycin significantly impaired the ability of 3A4 to efficiently metabolize the pimozide. predisposing to a torsades de pointes arrhythmia. he began to experience increasing fatigue. Clin Pharmacol Ther 65:10–20. 1998 Desta Z. Kerbusch T. when the pimozide blood level increased. John’s wort (Hypericum perforatum) and began taking it at the dosage indicated by the pharmacist. . Pimozide is a 3A4 substrate (Desta et al. He was started on cyclosporine (Sandimmune) so that his immune system would not reject his new heart. He began to experience some depressive symptoms (moderate dysphoria. poor appetite. When he reported these symptoms to his cardiologist. believing that this would be a healthier alternative to the usual antidepressants. Thus. J Pharmacol Exp Ther 285:428–437. Hence. Kerbusch T. he wanted to take a natural remedy for depression. insomnia. there was a pharmacodynamic interaction (additive QTc interval prolongation) in addition to the pharmacokinetic one (3A4 inhibition). leading to ventricular fibrillation and death. Flockhart DA: Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). he was admitted to the hospital.

References Hennessy M. Meier PJ. et al: St Johns wort increases expression of Pglycoprotein: implications for drug interactions. 2002 Kronbach T. Higashi Y. Br J Clin Pharmacol 53:75–82. Because the cyclosporine was inhibiting the patient’s immune response to the foreign donor heart. John’s wort is a P-glycoprotein inducer (Hennessy et al. 2002). Shimada T. John’s wort increased the number of P-glycoprotein transporters and hence increased the overall activity of P-glycoprotein. Anderson GD. John’s wort: effect on CYP3A4 activity. et al: Modulation of mdr1a and CYP3A gene expression in the intestine and liver as possible cause of changes in the cyclosporin A disposition kinetics by dexamethasone. Cyclosporine is a P-glycoprotein substrate (Yokogawa et al. et al: St. Kantor E. John’s wort. Jones SA. John’s wort was added to the cyclosporine. 2000. there was an increase in the amount of 3A4 available to metabolize the cyclosporine. which led to more cyclosporine being extruded from enterocytes back into the gut lumen. 2002 . John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Thus. 2000 Yokogawa K. Spiers JP. When the St.114 Drug–Drug Interaction Primer Discussion This is an example of an inducer added to a substrate. Proc Natl Acad Sci USA 97:7500–7502. 2000 Ruschitzka F. et al: Acute heart transplant rejection due to Saint John’s wort (letter). Lancet 355:548–549. Clin Pharmacol Ther 67:451–457. 2002). Goodwin B. John’s wort is a 3A4 inducer (Moore et al. 1988 Moore LB. There is also a likely contribution to this decrease in cyclosporine blood level from alterations in the functioning of the P-glycoprotein transporter. where it was excreted rather than absorbed. Roby et al. et al: St. Fischer V. and St. 2000). Biochem Pharmacol 63:777–783. and St. 1988). This increase in excretion and decrease in absorption of cyclosporine also contributed to the decrease in the cyclosporine blood level following the addition of St. Clin Pharmacol Ther 43:630–635. this decrease in the cyclosporine blood level led to a reactivation of his immune response and the resulting organ rejection. Over the next several weeks. Kelleher D. this led to more efficient metabolism of the cyclosporine and a resultant decrease in the blood level of cyclosporine from its previous baseline level. 2000 Roby CA. Meyer UA: Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporinemetabolizing enzyme explains interactions of cyclosporine with other drugs. Cyclosporine is a 3A4 substrate (Kronbach et al. the St. Turina M.

the patient remained unconscious almost 3 hours longer than the average patient. 1997 von Moltke LL. His only medications were diltiazem (Cardizem) for hypertension and a multivitamin. 1996). 2000 Sutton D. Because this was the final “scope” of the day. von Moltke et al. et al: Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. References Ahonen J. and by azole antifungal agents. The colonoscopy proceeded uneventfully. Clin Pharmacokinet 38:41–57. and diltiazem is a competitive inhibitor of 3A4 (Sutton et al. 1997). Because the diltiazem was present. the patient needed his spouse to come and drive him home because of residual sedation. 1996 . but following the procedure. This resulted in a blood level of midazolam that was significantly higher than expected. Greenblatt DJ. Olkkola KT. Midazolam was administered in a standard dose that did not take into account the presence of a significant 3A4 inhibitor. Butler AM. J Clin Pharmacol 36:783–791. Spence JD. Anesthesiology 85:1246–1252. this interaction has resulted in significant delays (2–3 hours) before patients could be safely extubated (Ahonen et al. Schmider J. Nadin L.Internal Medicine Case Vignettes 115 SEDATION. In some surgical procedures in which intubation is required. TERMINABLE AND INTERMINABLE A 40-year-old man was referred by his internist to a gastroenterologist for his first-ever screening colonoscopy. Even then. Salmenpera M. Discussion This is an example of a substrate added to an inhibitor. this obligated the gastroenterologist and a nurse to wait with the patient until he finally woke up. the ability of 3A4 to efficiently metabolize the midazolam was significantly impaired. The gastroenterologist typically used midazolam (Versed) as his sedative agent during this procedure. et al: Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine. which yielded excessive sedation and much inconvenience for all concerned. Midazolam is a 3A4 substrate (Dresser et al. 2000. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. J Pharmacol Exp Ther 282:294–300. 1996). et al: Effect of diltiazem on midazolam and alfentanil disposition in patients undergoing coronary artery bypass grafting. 1996 Dresser GK. norfluoxetine.

Rifampin is a “paninducer. potentially requiring several hundred milligrams per day. Discussion This is an example of an inducer added to a substrate. Kantola T. Clin Pharmacol Ther 62:348–354. and an area under the curve that is only 15% of baseline (Kivisto et al. the internist reassessed the patient’s medication regimen and consulted his hospital pharmacist. Within the next 2 weeks. including 3A4 (Strayhorn et al. which provided symptomatic relief. Lamberg TS. Among other medications. 1997).” which means that it induces virtually all of the major P450 enzymes. the internist referred the patient to a psychologist for supportive counseling. When the pharmacist shared this information with the internist. Lamberg TS. References Kivisto KT. 1999). Self TH: Update on rifampin drug interactions. et al: Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole. Arch Intern Med 157:2453–2458. and a workup eventually revealed active tuberculosis. III.5 mg bid. Neuvonen PJ: Interactions of buspirone with itraconazole and rifampicin: effects on the pharmacokinetics of the active 1-(2-pyrimidinyl)-piperazine metabolite of buspirone. which eventually provided significant relief for the patient’s anxiety when titrated to a dosage of 1. The addition of rifampin led to an increased amount of 3A4. and he instead chose to add clonazepam. Pharmacol Toxicol 84:94–97. The answer he received prompted him to add clonazepam (Klonopin). He visited his internist. Initially interpreting the patient’s increased anxiety as being related to his recently finding out about the tuberculosis. 60 mg/day. Buspirone is a 3A4 substrate (Kivisto et al. 1999 Strayhorn VA.116 Drug–Drug Interaction Primer TUBERCULOUS ANXIETY A 35-year-old man diagnosed with generalized anxiety disorder (GAD) was receiving good benefit from buspirone (BuSpar). When this did not prove helpful. This resulted in a greatly decreased blood level of buspirone within 1–2 weeks of starting the rifampin. 1997 . Studies have demonstrated that this specific interaction may result in maximum buspirone blood levels that are only 9% of baseline values. he experienced greatly heightened generalized anxiety. he was placed on rifampin (in the form of Rifadin) at standard dosages. which led to a relapse of the patient’s active GAD symptoms. 1997 Kivisto KT. After traveling abroad for several months. which led to more efficient metabolism of the buspirone. the internist wisely decided that treating the patient’s anxiety by increasing the dosage of buspirone would have been impractical. he began to experience a frequent and painful dry cough as well as malaise and intermittent fever. 1997). Baciewicz AM.

even though the dosage had not been changed (DeVane and Nemeroff 2002). 2002 Dresser GK. These medications had generally pro- . 2000). the patient’s alprazolam dosage of 1 mg tid provided relief from panic attacks without producing excessive sedation. and clarithromycin is a strong competitive inhibitor of 3A4 (Desta et al. 1 mg tid. This led to her increasing daytime sedation. Over the next several days. 150 mg/day. culminating in her car crash. 1999). Clin Pharmacol Ther 65:10–20. 500 mg bid. Her painful coughing and fever prompted her to visit her internist. and alprazolam. Alprazolam is a 3A4 substrate (Dresser et al. During the ride home. who prescribed clarithromycin. At baseline. 1 mg tid. she was prevented from sleeping by her newborn child. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. the ability of 3A4 to efficiently metabolize the alprazolam was significantly impaired. Flockhart DA: Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). Spence JD. 1999 DeVane CL. with the addition of the clarithromycin.Internal Medicine Case Vignettes 117 CRASH A 38-year-old woman with chronic panic disorder had responded well to a regimen of venlafaxine (Effexor). References Desta Z. Discussion This is an example of an inhibitor added to a substrate. 2000 DROWSY DOG TRAINER A 42-year-old woman who worked as a dog trainer was receiving alprazolam (Xanax). Clin Pharmacokinet 38:41–57. and citalopram (Celexa). On the night of day 4 of her clarithromycin regimen. having taken her final alprazolam dose of the day at 6 PM. 20 mg/day. from her psychiatrist for treatment of anxious depression. she fell asleep at the wheel and crashed her car into a tree. Nemeroff CB: 2002 guide to psychotropic drug interactions. Prim Psychiatry 9:28–57. who also had an upper respiratory infection. One winter she developed bronchitis. she experienced increasing fatigue and sedation. However. resulting in a significantly increased blood level of alprazolam. She then drove to her job and worked until 7 PM. for 10 days. Kerbusch T.

the psychiatrist changed her alprazolam to lorazepam (Ativan). Her psychiatrist addressed this by changing from alprazolam to a benzodiazepine (lorazepam) that does not rely on P450 enzymes for its metabolism. Her internist prescribed. Her despair over this event and her unremitting sedation led her to contact her psychiatrist. 2000). 1998) as well as a “pan-inhibitor” of all major P450 enzymes except for 1A2 and 2E1 (von Moltke et al. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. when ritonavir’s specific 3A4 induction profile was able to offset its inhibitory profile. Because ritonavir becomes a specific inducer of 3A4 after a few weeks (Piscitelli et al. During a life insurance physical examination with screening laboratory studies. she discovered that she was HIV positive. which would suggest the need for a larger alprazolam final dosage. ritonavir’s interaction with meperidine (Demerol) (see “Induction Toxicity” in Chapter 5) suggests that ritonavir’s 3A4 induction effect overtakes the inhibitory effect. Alprazolam is a 3A4 substrate (Dresser et al. Clin Pharmacokinet 38:41–57. 1998). Spence JD. resulting in an increase in the blood level of alprazolam despite no change in the dosing of the alprazolam (K. Cozza. but rather on phase II glucuronidation. The final alprazolam dosage could well be close to (or identical to) the original dosage before the addition of ritonavir. and therefore did not walk the dogs that she was scheduled to walk that day. One week after starting the ritonavir. The addition of ritonavir to the patient’s regimen impaired the ability of 3A4 to efficiently metabolize the alprazolam. Discussion This is an example of an inhibitor added to a substrate. but there is no way to predict this. 2000 . an alternative management strategy would have been to temporarily decrease the dosage of alprazolam to clinical effect when ritonavir’s early 3A4 inhibitory effects predominated. 2000). 1 mg tid. If anything. slept through her alarm.118 Drug–Drug Interaction Primer vided relief for her symptoms. Her disgruntled clients promptly fired her.L. the alprazolam dosage could again be increased to clinical effect. personal communication. among other medications. Ritonavir is a potent 3A4 inhibitor (Iribarne et al. A few weeks later. References Dresser GK. decreasing and increasing the alprazolam dosage would need to be based on clinical response and side effects. the protease inhibitor ritonavir (Norvir). This led to the patient’s subsequent sedation. she felt so drowsy that she took a midafternoon nap. After reviewing recent developments. The sedation remitted and she enjoyed a satisfactory clinical response. If one wished to adopt this strategy. May 2002).

who examined the patient and ran numerous tests before eventually diagnosing her with a Legionella pneumonia. 1997). 1997 . 1998 Piscitelli SC. and weakness. One winter. for several years. Greenblatt DJ. After her erythromycin course was completed. The addition of the erythromycin impaired the efficient metabolism of buspirone by 3A4. et al: Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. her buspirone dosage would be titrated back to 30 mg bid. leading to an increased blood level of buspirone despite an initially constant buspirone dosage. 1998 LEGIONNAIRE A 47-year-old woman with generalized anxiety disorder had responded well to buspirone (BuSpar). With the completion of the erythromycin course and the cessation of 3A4 inhibition. the buspirone dose could again return to 30 mg bid. She followed his instructions. She consulted her psychiatrist. she developed a persistent dry cough. J Clin Pharmacol 38:106–111. Berthou F. Buspirone is a 3A4 substrate (Kivisto et al. 750 mg every 6 hours. and psychomotor slowing. the patient’s respiratory symptoms were significantly improved. Bertz RJ. et al: Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole.Internal Medicine Case Vignettes 119 Iribarne C. headache. References Kivisto KT. Some studies have indicated that the buspirone level may increase sixfold or more when buspirone is combined with erythromycin (Kivisto et al. 2000). 1997). for the duration of her treatment with erythromycin. Lamberg TS. et al: Inhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors. but she then developed severe sedation. Pharmacotherapy 20:549–553. 2000 von Moltke LL. Within 4 days. et al: The effect of ritonavir on the pharmacokinetics of meperidine and normeperidine. Drug Metab Dispos 26:257–260. 5 mg bid. The psychiatrist’s suggested decrease in buspirone dosage compensated for this interaction. Carlhant D. and her treatment course proceeded uneventfully. He started the patient on erythromycin (E-mycin). Kantola T. 30 mg bid. Grassi JM. persistent headache. nausea. Clin Pharmacol Ther 62:348–354. Discussion This is an example of an inhibitor added to a substrate. She visited her internist. Kress DR. who held her buspirone for 1 day and then instructed her to take buspirone. low-grade fever. and erythromycin is a competitive inhibitor of 3A4 (Pai et al.

when the patient did not come to the unit kitchen for breakfast. and then death. and ketoconazole is a very strong competitive inhibitor of 3A4 (Boxenbaum 1999). et al: Identification and characterization of human cytochrome P450 isoforms interaction with pimozide. J Pharm Pharm Sci 2:47–52. This led to a sharp increase in the blood level of pimozide. He was admitted to the psychiatric inpatient unit. Ann Pharmacother 34:495–513. the increase in the pimozide blood level caused a lengthening of the QTc interval. One week later. to be given for at least 6 months. 1999 Desta Z. Amsden GW: Macrolide drug interactions: an update. He was not arousable. May 2002). 200 mg/day. 1999). staff went to the patient’s room to wake him. A workup eventually revealed that he had a pulmonary histoplasmosis infection. ventricular fibrillation.L. personal communication. 4 mg/day. Although a code was called. Graci DM. Pimozide is a 3A4 substrate (Desta et al. References Boxenbaum H: Cytochrome P450 3A4 in vivo ketoconazole competitive inhibition: determination of Ki and dangers associated with high clearance drugs in general. and his pimozide was restarted. which likely led to the development of a torsades de pointes arrhythmia (Dresser et al.120 Drug–Drug Interaction Primer Pai MP. and his various HIV-related medications. even though the dosage of pimozide had not been changed. J Pharmacol Exp Ther 285:428–437. Discussion This is an example of an inhibitor added to a substrate. He was eventually brought to a local emergency room by the police after they found him standing in the middle of the street shouting and preaching at pedestrians and severely blocking traffic. it was clear that he had died several hours earlier (K. Kerbusch T. Cozza. Soukhova N. 1998 . 1998. Because pimozide prolongs the QTc interval on the electrocardiogram in a dosedependent manner. 2000). The addition of ketoconazole significantly impaired the ability of 3A4 to efficiently metabolize the pimozide. 2000 FUNGAL FATALITY A 32-year-old HIV-positive man with schizophrenia had been noncompliant with his pimozide (Orap). He was noted to have a persistent cough and low-grade fevers. The consulting internist prescribed ketoconazole (Nizoral).

he would likely have generated a higher midazolam blood level and accordingly encountered more-than-typical sedation following standard dosing of midazolam. 2000.to moderate-strength 3A4 inhibitor (Iribarne et al. to the point that he eventually required the administration of a benzodiazepine antagonist to awaken. Discussion This is an example of a substrate added to an inhibitor. Flockhart DA: Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). Midazolam is a 3A4 substrate (Dresser et al. at which time they administered flumazenil (Mazicon) to reverse his sedation (Merry et al. When he was discussing his extended period of sedation with one of the nurses. Kerbusch T. . It also appears from his history that the patient may be an inefficient 3A4 metabolizer. after having waited more than 5 hours postbronchoscopy. This does not imply that he is a poor metabolizer at 3A4 (there are none such. Therefore.” the metabolism of midazolam was further slowed. However. He recounted that roughly 10 years earlier (before he began taking saquinavir). who was taking saquinavir (Fortovase). because he was possibly a less active 3A4 metabolizer than most persons. who (possibly) had little 3A4 “reserve. 1997). with the addition of even a mild to moderate 3A4 inhibitor in this individual. he had tried one of his girlfriend’s alprazolam (Xanax) pills one morning and had felt “really tired and spacey” for the rest of that day. Clin Pharmacol Ther 65:10–20. was having a bronchoscopy to evaluate some concerning masses noted on both a chest X ray and a computed tomography scan of the chest. the patient did not awaken in the first hour after the procedure. 1999 Dresser GK. and his midazolam blood level further increased. von Moltke et al. and saquinavir is a mild. he remarked that he had always been “sensitive” to some medications. Finally. as this would often be incompatible with life) but rather that he may be one of those individuals at the low end of the estimated 10. Spence JD. However.to 30-fold variability in the efficiency of 3A4 across the human species (Ketter et al. The postoperative staff continued to wait for his sedation to abate. 2000 PATIENCE A 43-year-old HIV-positive man. 1996). Clin Pharmacokinet 38:41–57. He was given a standard dose (10 mg) of intravenous midazolam (Versed) throughout the course of the procedure. 1998). their patience was exhausted. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. 1995).Internal Medicine Case Vignettes 121 Desta Z.

This resulted in a . titrating the drug to a dosage of 600 mg/day over the course of 3 weeks. and fever. Post RM. reporting worsening terminal insomnia. 1996). who advised the patient to go to an emergency room immediately. which led to an increase in the blood level of simvastatin. he became increasingly anxious and depressed. the patient experienced worsening myalgias. 1996 STYMIED BY STATINS (II) A 57-year-old man with hypercholesterolemia was taking simvastatin (Zocor) to address this. After some discussion with the patient. Berthou F. Clin Pharmacokinet 38:41–57. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. et al: Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine. Flockhart DA. Drug Metab Dispos 26:257–260. anergy. The internist had heard that nefazodone (Serzone) was helpful for anxious depression and especially helpful for insomnia.7 mg/dL.000 IU/L and a serum creatinine level of 2. Greenblatt DJ. Carlhant D. The addition of nefazodone significantly impaired the ability of 3A4 to metabolize the simvastatin. Mulcahy F. muscle weakness. Neuvonen et al. Barry M. J Clin Psychopharmacol 15:387–398. Ruths. he was found to have a creatine phosphokinase level above 2. 1998 Ketter TA. Simvastatin is a 3A4 substrate (Gruer et al. 1995 Merry C. In the emergency room. et al: Inhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors. poor appetite. and his urine output declined sharply. personal communication. and poor concentration to his internist. Schmider J. 2000 Iribarne C. even though the dosage had not changed. and nefazodone is a strong competitive inhibitor of 3A4 (von Moltke et al. In the week after reaching this dosage. Spence JD. June 2002). AIDS 11:268–269. 1998). he prescribed nefazodone. After his father passed away. J Clin Pharmacol 36:783–791. Discussion This is an example of an inhibitor added to a substrate. 1997 von Moltke LL. norfluoxetine. and by azole antifungal agents. He reported these symptoms to his internist.122 Drug–Drug Interaction Primer References Dresser GK. 1999. et al: Saquinavir interaction with midazolam: pharmacokinetic considerations when prescribing protease inhibitors for patients with HIV disease. et al: The emerging role of cytochrome P450 3A in psychopharmacology. He was diagnosed with rhabdomyolysis-induced acute renal failure (S.

Mercuri MF. References Gruer PJ. she was feeling much better. and she displayed no focal neurological signs. 1997). He sent the patient home with instructions to check in with his office daily.5-fold increase in the . 1998 von Moltke LL. After she reported these symptoms to the internist. et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole.Internal Medicine Case Vignettes 123 state of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitor toxicity. resulting in her lethargy and clumsiness. J Pharmacol Exp Ther 276:370–379. 30 mg/day. 1999 Neuvonen PJ. Greenblatt DJ. her internist noted that her blood pressure had continued to steadily rise with age. Her blood pressure was not unduly low. 30 mg/day. During a routine checkup. Harmatz JS. Although he was not aware of a specific interaction between diltiazem and her psychiatric medications. the patient experienced growing lethargy and incoordination. Kantola T. he prescribed diltiazem (Cardizem) and scheduled a follow-up appointment in 1 month. Am J Cardiol 84:811–815. Within 36 hours. One study demonstrated a 5. within 3 days. This led to an increase in the blood level of buspirone. The addition of the diltiazem significantly impaired the ability of 3A4 to efficiently metabolize the buspirone. 1996 CLUMSY A 56-year-old woman with recurrent anxious depression had done well for several years on the regimen of mirtazapine (Remeron). Discussion This is an example of an inhibitor added to a substrate. 1997). Clin Pharmacol Ther 63:332–341. Vega JM. which led to her frequently bumping into furniture and walls. and diltiazem is a competitive inhibitor of 3A4 (Sutton et al. Kivisto KT: Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. which in this case led to such extensive rhabdomyolysis that it overwhelmed the patient’s renal function. and buspirone (BuSpar). et al: Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. After some discussion. the chronology seemed to implicate this as the likely cause of her difficulties. However. he instructed her to discontinue the diltiazem and to come to his office that day. Buspirone is a 3A4 substrate (Kivisto et al. even though the dosage of buspirone had not been changed.

1997 Lamberg TS. 3A4 resumed its baseline (higher) level of metabolic activity. there was much more 3A4 available to metabolize the zolpidem than was expected. Once the diltiazem was discontinued. but this did not help him get to sleep. 1998). J Pharmacol Exp Ther 282:294–300.124 Drug–Drug Interaction Primer buspirone area under the curve with the addition of diltiazem (Lamberg et al. Kivisto KT. Zolpidem is principally a substrate of 3A4 (von Moltke et al. because rifampin was already present. The next night. After he reported these events to his internist. 1997). He would often dwell on these as he tried to get to sleep. Kantola T. However. he continued to increase the dosage. and he still did not feel at all drowsy. the buspirone blood level declined back to baseline. References Kivisto KT. which did reliably help him to fall asleep. 1999). 5–10 mg qhs prn for insomnia. and the patient’s side effects remitted. Studies have shown that rifampin can reduce zolpidem’s area under the curve to 27% of its baseline value and its maximum concentration to 42% of its . 1997 RESTLESS A 32-year-old man who was receiving rifampin (in the form of Rifadin) as treatment for tuberculosis was having increasing difficulties with his relationships. and he was prescribed zolpidem (Ambien). Butler AM. et al: Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. with the result that the zolpidem blood level at a dosage of 10 mg was far too low to promote sleep. He asked his internist for a sleep aid. Nadin L. Clin Pharmacol Ther 63:640–645. 1998 Sutton D. he was instead prescribed gabapentin (Neurontin). Discussion This is an example of a substrate added to an inducer. Neuvonen PJ: Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics of buspirone. for the insomnia. Clin Pharmacol Ther 62:348–354. He found that only after he took a dose of at least 25 mg was he able to fall asleep promptly. Without consulting his internist. 300 mg po qhs as needed. et al: Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole. The following night he tried 10 mg of zolpidem. and rifampin is a strong 3A4 inducer (Strayhorn et al. Lamberg TS. he tried the 5-mg dose of zolpidem. The zolpidem was initially prescribed at a dosage that would generally help facilitate sleep. leading to persistent onset insomnia.

0 mg/dL. 1997 von Moltke LL. Therefore. Br J Clin Pharmacol 48:89–97. insomnia. from 0. 1997 Villikka K. When the nefazodone was added. Her nephrologist decided to prescribe nefazodone (Serzone). Granda BW.9 mg/dL. et al: Zolpidem metabolism in vitro: responsible cytochromes. chemical inhibitors. 1996). and sedation. et al: Rifampin reduces plasma concentrations and effects of zolpidem. even at such a low dosage (50 mg bid) of . 50 mg bid initially. Greenblatt DJ. III.Internal Medicine Case Vignettes 125 baseline value (Villikka et al.8 mg/dL to 1. Tacrolimus is a 3A4 substrate (Olyaei et al. She was brought to the emergency room and admitted to the hospital. the patient experienced a coarse upper extremity tremor. Once the internist became aware of this situation. Her tacrolimus level had risen to 28. anhedonia. Arch Intern Med 157:2453–2458. confusion. Self TH: Update on rifampin drug interactions. Kivisto KT. after only 1 week of taking the initial 50-mg-bid dosage of nefazodone. and her serum creatinine level had also risen. and poor energy at that time. 1998). because rifampin is a “pan-inducer” across most major P450 enzymes. and she was being stably maintained on the immunosuppressant regimen of prednisone and tacrolimus (Prograf). she was experiencing increasing anxiety. 1999 OVERSUPPRESSION A 62-year-old woman had undergone successful renal transplantation 6 months ago. Baciewicz AM.8 ng/mL. Her nefazodone was then abruptly discontinued and the tacrolimus was held for 2 days. In less than 1 week. Clin Pharmacol Ther 62:629–634. her tacrolimus level was again at baseline and her creatinine level was 1. and in vivo correlations. References Strayhorn VA. and nefazodone is a competitive inhibitor of 3A4 (von Moltke et al. to compensate for the greater level of 3A4 activity due to induction by the rifampin. In the context of marital difficulties and numerous medical concerns. with a plan to titrate to a dosage of 400 mg/day. poor appetite. he switched to a sedating agent (the anticonvulsant gabapentin) that did not rely on P450-based metabolism. the ability of 3A4 to efficiently metabolize the tacrolimus was significantly impaired. dysphoria. However. 1997). Luurila H. titrated to levels between 12 and 16 ng/mL. that he was able to fall asleep. it was only after the patient increased the dosage of the zolpidem. Discussion This is an example of an inhibitor added to a substrate.

References Arima H. Perloff MD. et al: Interaction between tacrolimus and nefazodone in a stable renal transplant recipient. 3A4 then resumed its higher baseline level of activity. Harmatz JS. This resulted in a state of tacrolimus toxicity. This resulting increase in the absorption of tacrolimus also contributed to the increase in the tacrolimus blood level following the addition of nefazodone. He independently decided to buy some St. et al: P-glycoprotein interactions of nefazodone and trazodone in cell culture. anhedonia. There is also a likely contribution to this increase in the tacrolimus blood level from alterations in the functioning of the P-glycoprotein transporter. J Pharmacol Exp Ther 276:370–379. where it would be excreted rather than absorbed. John’s wort (Hypericum perforatum) over the counter. 2001 Olyaei AJ. von Moltke LL. the nefazodone decreased the activity of P-glycoprotein. and nefazodone is an acute P-glycoprotein inhibitor (when chronically administered. Thus. Yunomae K. 1996 NATURAL DISASTER (II) A 35-year-old HIV-positive man was being maintained on nevirapine (Viramune). insomnia. Hirayama F. with reasonably good control of his illness and good CD4 counts. and he began to experience frequent fevers. and he began taking it as directed by the pharmacist. it also functions as a P-glycoprotein inducer) (Stormer et al. and sedation. even though the tacrolimus dosage had not been changed (Olyaei et al. Over the next 3 months. among other medications. 2001 von Moltke LL. as well as the stresses of his HIV diagnosis. et al: Contribution of P-glycoprotein to the enhancing effects of dimethyl-beta-cyclodextrin on oral bioavailability of tacrolimus. 2001). This led to a higher blood level of tacrolimus. characterized by confusion (delirium). Tacrolimus is a P-glycoprotein substrate (Arima et al. he felt increasingly fatigued and developed a persistent cough. His cough grew painful.126 Drug–Drug Interaction Primer nefazodone. he began to experience increasing dysphoria. 1998). 2001). which led to less tacrolimus being extruded from enterocytes back into the gut lumen. Greenblatt DJ. Norman DJ. Pharmacotherapy 18:1356–1359. He re- . J Pharmacol Exp Ther 297:547–555. deMattos AM. and lack of energy. et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. J Clin Pharmacol 41:708–714. tremor. Because of a recent breakup with his significant other. leading to a decrease of the tacrolimus blood level back to its baseline and a remission of her toxicity state. 1998 Stormer E. After the nefazodone was removed.

which he began to take per the package instruc- . John’s wort is a 3A4 inducer (Moore et al. An array of psychosocial stressors and ruminative somatic concerns led him to a state of increasing dysphoria. John’s wort. with accompanying insomnia. Once the patient was admitted to the medical floor. and fatigue. it was found that his CD4 counts were significantly decreased and his viral load numbers were elevated compared with those obtained at his last office visit. Once in the emergency room. the amount of 3A4 available to metabolize the nevirapine significantly increased. He decided to buy some over-the-counter St. Jones SA. Roby et al. 2001 INHIBITOR INDUCTION A 24-year-old HIV-positive man was taking numerous medications for his illness. Not only did the patient develop P. Kantor E. the metabolism of the nevirapine was induced to the extent that the nevirapine blood level became subtherapeutic. 2000 Roby CA. who instructed him to report to the nearest emergency room. a protease inhibitor. including indinavir (Crixivan). Proc Natl Acad Sci USA 97:7500–7502.Internal Medicine Case Vignettes 127 ported these symptoms to his internist. 2002 Moore LB. 2000 St. “St. Xenobiotica 32:451–478. anxiety. Goodwin B. et al: St. 2000. References Ioannides C: Pharmacokinetic interactions between herbal remedies and medicinal drugs. Clin Pharmacol Ther 67:451–457. the patient had a chest X ray consistent with a diagnosis of Pneumocystis carinii pneumonia. poor concentration. In this case. John’s wort (Hypericum perforatum). John’s wort: effect on CYP3A4 activity. carinii pneumonia and worsening viral loads and CD4 counts. John’s Wort Found to Lower Nevirapine Levels” 2001). With the addition of the St. with the result that the blood level of nevirapine was significantly decreased (Ioannides 2002. and St. 2000). John’s wort found to lower nevirapine levels. but exposing the patient in a sustained manner to a subtherapeutic nevirapine blood level could actually foster the development of resistant HIV strains and thus decrease the future ability to treat the illness in this particular individual. Discussion This is an example of an inducer added to a substrate. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Anderson GD. Nevirapine is a 3A4 substrate (Ioannides 2002). et al: St. and thus the nevirapine became ineffective at halting or slowing the progression of AIDS. Treatment Update 12:6.

John’s wort to indinavir can produce mean indinavir concentrations that are only 43% of baseline and trough indinavir blood levels that are only 19% of baseline (Piscitelli et al. his CD4 counts had dropped precipitously. and St. Discussion This is an example of an inducer added to a substrate. Indinavir is a 3A4 substrate (Barry et al. Proc Natl Acad Sci USA 97:7500–7502. 2001). et al: Indinavir concentrations and St. References Barry M. Roby et al. Kelleher D. This increase in excretion and decrease in absorption of indinavir also likely contributed to the decrease in the blood level of indinavir following the addition of St. John’s wort. 2000). John’s wort increased the activity of P-glycoprotein. et al: Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. John’s wort. Spiers JP. Br J Clin Pharmacol 53:75–82. 2000 . Mulcahy F. which led to more indinavir being extruded from enterocytes back into the gut lumen. Indinavir is a P-glycoprotein substrate (van der Sandt et al. At his next appointment with his internist (3 months later). John’s wort. the patient then informed him about his decision to begin taking St. et al: St. Thus.128 Drug–Drug Interaction Primer tions. this led to an increase in the amount of 3A4 that was available to metabolize the indinavir. 2002 Moore LB. Studies have demonstrated that the addition of St. Chaitt D. protracted exposure to subtherapeutic concentrations of a protease inhibitor could predispose the patient to develop resistant strains of HIV. As a result. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Merry C. 2002). Jones SA. et al: St Johns wort increases expression of Pglycoprotein: implications for drug interactions. There is also a likely P-glycoprotein contribution to this interaction. John’s wort is a P-glycoprotein inducer (Hennessy et al. with a subsequent decrease in the patient’s CD4 count and an increase in his viral load. 2000 Piscitelli SC. When the internist asked about any recent life changes that might explain these findings. When the St. the St. and St. Goodwin B. where it was excreted rather than absorbed. Clin Pharmacokinet 36:289–304. Further testing revealed both an increased viral load and a decreased indinavir blood level. Furthermore. Burstein AH. 1999). John’s wort is a 3A4 inducer (Moore et al. 1999 Hennessy M. 2000). there was a decrease in the indinavir blood level to the subtherapeutic range. John’s wort was added to the indinavir. 2000. Lancet 355:547–548.

In this case. 500 mg qid for 10 days. Chesley S. The addition of erythromycin markedly impaired the ability of 3A4 to make a significant contribution to the overall metabolism of clozapine. Kantor E. the increase in the clozapine blood level led to increased sedation and sialorrhea (hypersalivation). Even though several P450 enzymes contribute to clozapine’s overall metabolism. which had risen to 737 ng/mL. 2001 SIALORRHEA A 45-year-old woman with paranoid schizophrenia had experienced a much more stable clinical course since starting clozapine (Clozaril). AIDS 15:483–491. Engel G. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Vos CM. 1997 . et al: Erythromycin-induced clozapine toxic reaction. with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. 1997. 1996). Arch Intern Med 156:675–677. 2000). She followed his instructions.Internal Medicine Case Vignettes 129 Roby CA. Erythromycin. One winter. 3A4’s role is sufficiently prominent that strong inhibition of this enzyme is able to reliably increase clozapine blood levels (Cohen et al. and she began salivating profusely at night. although no further blood levels were obtained at that time. She reported these symptoms to both her internist and her psychiatrist. however. Eugenio L. Clin Pharmacol Ther 67:451–457. Her psychiatrist suggested that she take only 300 mg/day of clozapine until the day after her erythromycin course was completed and then resume her normal clozapine dosing. Nabulsi L. Her psychiatrist ordered an immediate clozapine blood level. Olesen and Linnet 2001). Johansson I. et al: Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood-brain barrier. she was experiencing some increased sedation as well as constipation. requiring that she change pillows two to three times per night. Br J Clin Pharmacol 44:439–446. et al: St. References Cohen LG. Anderson GD. Discussion This is an example of an inhibitor added to a substrate. Clozapine’s metabolism occurs primarily at 1A2. John’s wort: effect on CYP3A4 activity. is a strong competitive inhibitor of 3A4 (Pai et al. and the remainder of her course was uneventful. The enzymes 3A4 and 2C19 are also significant contributors. 500 mg/day (blood level generally around 450 ng/mL). 1996 Eiermann B. By day 5. 2000 van der Sandt IC. The effect of adding erythromycin to clozapine is variable in magnitude. she developed a case of bronchitis and her internist prescribed erythromycin (E-mycin).

for which he prescribed itraconazole (Sporanox). By day 5 of the first week of itraconazole use. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. then another week of treatment. Despite these events. to be followed by a 3-week hiatus. Discussion This is an (especially tragic) example of an inhibitor added to a substrate. The addition of the itraconazole significantly impaired the ability of 3A4 to efficiently metabolize the triazolam. the patient nonetheless opted to take 0. 2000 . Triazolam is a 3A4 substrate. as are all the other triazolobenzodiazepines. which led to a significant increase in the blood level and half-life of triazolam. 2000 AVOIDABLE TRAGEDY A 47-year-old woman with recent sleep difficulties had been taking triazolam (Halcion). and she was indeed more alert the next day. In the course of that drive. Graci DM. 0.130 Drug–Drug Interaction Primer Olesen OV. with slurring of her speech and ataxia. Itraconazole is a potent competitive inhibitor of 3A4 (von Moltke et al. She also developed a pedal onychomycosis. J Clin Pharmacol 41:823–832. She contacted her neurologist. who advised her to hold her triazolam that night. August 2002). Love. 1995) to over 24 hours (Varhe et al. 2000). It has been demonstrated that itraconazole can lengthen the half-life of triazolam from 1. Spence JD. the patient was experiencing significant daytime sedation. Clin Pharmacokinet 38:41–57. including midazolam (Versed) and alprazolam (Xanax) (Dresser et al.5 mg qhs. even though the dosage of triazolam had not been changed. personal communication. 1994). this effect accounted for the patient’s severe daytime sedation and the subsequent tragedy.25–0. Ann Pharmacother 34:495–513. 200 mg bid for the first week. prescribed by her family physician. the patient fell deeply asleep at the wheel. In this case. Amsden GW: Macrolide drug interactions: an update.5–5 hours (Hyman et al. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. References Dresser GK. 2001 Pai MP.375 mg of her triazolam that very night. crossing four lanes of traffic and the median barrier before crashing into a car heading the opposite direction. She needed to make a 2-hour drive the following day. 1996). killing herself and both persons in the other vehicle (R.

500 mg qid for 10 days. Arana GW. the addition of erythromycin impaired the ability of 3A4 to contribute to the efficient metabolism of carbamazepine.000 mg/ day (blood level. Spina et al.3 µg/mL) of carbamazepine (Tegretol) for the treatment of bipolar I disorder. J Pharmacol Exp Ther 276:370–379. 5 days after the discontinuation of the erythromycin. Boston. She did not encounter any additional problems with the remainder of her erythromycin course. She was discovered by her boyfriend. 2000). She was admitted to the hospital. 2B6.9 µg/mL.Internal Medicine Case Vignettes 131 Hyman SE. The patient experienced increasing sedation and ataxia over the next several days. 1995 Varhe A. the patient experienced the first and only seizure of her life. 2002. 2004). Little. Olkkola KT. with 1A2. Rosenbaum JF: Handbook of Psychiatric Drug Therapy. where her carbamazepine blood level was found to be 20. 1996 THE SPIRIT OF INQUIRY A 28-year-old woman was receiving 1. and her internist prescribed erythromycin (E-mycin). personal communication. et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. but no one contacted the prescribing psychiatrist. One winter. and phase II metabolism (uridine 5′-diphosphate glucuronosyltransferase [UGT] 2B7) making minor contributions to carbamazepine’s metabolism (Pearce et al. She was taken to the nearest emergency room. However. where her carbamazepine blood level was found to be 4. and on day 5 of this regimen she experienced a fall without loss of consciousness.1 µg/mL (R. Discussion This is an example of an inhibitor added to a substrate followed by reversal of inhibition. Clin Pharmacol Ther 56:601–607. 9. 2C8/9. Rather. 1994 von Moltke LL. Initially. Harmatz JS. who called an ambulance to again take her to the nearest emergency room. inquired as to her baseline carbamazepine blood levels at given dosages. she contracted bronchitis. Greenblatt DJ. her carbamazepine was empirically decreased to 500 mg/day. MA. 2E1. Carbamazepine is primarily a 3A4 substrate. Staines et al. Because the activity of 1A2 and 2C9 was not suffi- . 3rd Edition. or even explored what led to the development of a toxic carbamazepine blood level. August 2002). Love. 1996. and she was discharged from the hospital after 2 days of taking the carbamazepine at this dosage. Brown. Erythromycin is a competitive inhibitor of 3A4 (Pai et al. Neuvonen PJ: Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole.

3A4 resumed its previous (higher) level of activity. this inhibition of 3A4 led to an increase in the blood level of carbamazepine.132 Drug–Drug Interaction Primer cient to compensate for this effect. Cai SH. Once this occurred. a P-glycoprotein-mediated interaction may have further potentiated the P450 component of this interaction. References Kiso S. Anticancer Res 20:2827–2834. Amsden GW: Macrolide drug interactions: an update. 2001). 2000 Pearce RE.and 3-hydroxylated metabolites. Whichever was the case. the hospitalist did not anticipate the reversal of inhibition that was to occur with the completion of the course of erythromycin. Vakkalagadda GR. and erythromycin is a P-glycoprotein inhibitor (Kiso et al. 2000 Pai MP. which led to an increased rate of metabolism of carbamazepine and a subsequent decline in the blood level of carbamazepine. even though the dosage of carbamazepine had not been increased. 2002 . Kitaichi K. Thus. Ann Pharmacother 34:495–513. which then further contributed to the resulting decrease in the carbamazepine blood level. Drug Metab Dispos 30:1170–1179. It was (and remains) unclear whether this seizure was entirely a product of her rapidly declining carbamazepine blood level or whether these fluctuations in carbamazepine blood level served to unmask a seizure disorder that had been subclinical until that time. where it would be excreted rather than absorbed. culminating in a fall. et al: Inhibitory effect of erythromycin on P-glycoproteinmediated biliary excretion of doxorubicin in rats. Subsequently. This rapid decline in the carbamazepine blood level led to a newonset seizure. who was well acquainted with the interaction of carbamazepine with erythromycin. Additionally. The resulting mild to moderate carbamazepine toxicity state manifested itself as sedation and ataxia. 2000). Carbamazepine is a P-glycoprotein substrate (Potschka et al. The cessation of the erythromycin course led to a reversal of these P-glycoprotein-mediated effects. Leeder JS: Pathways of carbamazepine bioactivation in vitro. This led to increased absorption of carbamazepine and thus an increase in the blood level of carbamazepine. I: characterization of human cytochromes P450 responsible for the formation of 2. although he did not determine why and how this situation had developed. much morbidity could have been avoided if either the patient or the medical team had contacted the psychiatrist. The hospitalist on the case compensated for the toxic carbamazepine blood level by decreasing the carbamazepine dosage. Graci DM. the addition of the erythromycin caused a decrease in the activity of P-glycoprotein in extruding carbamazepine from enterocytes back into the gut lumen.

Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. 2001 Spina E. and 1A2 (Martinez et al. 2D6.” He was eventually referred to an ear. and CYP3A by H2-receptor antagonists. This led to an increase in the blood level of erythromycin. References Abbott Laboratories: Erythromycin (package insert). the addition of the cimetidine significantly impaired the ability of 3A4 to metabolize erythromycin. Oesterheld.to 60-decibel hearing loss (J. occasional shortness of breath. for the past 2 years with reasonably good results. Over the course of the next 5 days. 300 mg qid. personal communication.000 mg bid. in the place of his previous ranitidine for cost reasons. Neuroreport 12:3557–3560. 1996 Staines AG. One winter. IL. where a chest X ray revealed an atypical pneumonia. 2000 Martinez C. and pleuritic chest pain. 150 mg bid. and throat specialist. Abbott Laboratories. Erythromycin is a 3A4 substrate (Abbott Laboratories 2000). He presented to a local emergency room. Coughtrie MW. 500 mg qid. Fedrowitz M. 2004 DEPARTED DECIBELS A 65-year-old man with moderate gastroesophageal disease had been taking ranitidine (Zantac). et al: Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2. Loscher W: P-glycoprotein and multidrug resistance– associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. CYP2D6. Discussion This is an example of an inhibitor added to a substrate. Thus. 1. fevers. Pisani F. Agundez JA. the patient’s pulmonary symptoms improved. J Pharmacol Exp Ther 311:1131–1137. the patient requested and received a prescription for cimetidine (Tagamet). Clin Pharmacokinet 31:198–214. nose. 1999 . Four days later.Internal Medicine Case Vignettes 133 Potschka H. 1999). and cimetidine is a “pan-inhibitor” that strongly inhibits 3A4. and erythromycin (E-mycin).R. He was started on oral amoxicillin (Trimox). Albet C. Burchell B: N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. but he complained about progressive “fuzzy hearing. who determined that the patient had likely suffered a bilateral 40. he developed persistent cough. July 2002). North Chicago. which led to erythromycin-induced ototoxicity. Clin Pharmacol Ther 65:369–376.

Martin J. and hypotension. 1999 NATURAL DISASTER (III) A 58-year-old man had just undergone a successful renal transplantation procedure. Backman JT. and an endocrinologist was consulted to address his sudden-onset adrenal insufficiency (Tiao et al. Discussion This is an example of reversal of inhibition. following which he was placed on standing prednisone (Deltasone) as an immunosuppressant. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. et al: Addisonian crisis in a liver transplant patient due to fluconazole withdrawal. Weber FL. Klotz U: Pharmacokinetic considerations in the treatment of inflammatory bowel disease. The presence of the fluconazole significantly impaired the ability of 3A4 to metabolize the prednisone. Niemi et al. This caused the patient to experience an acute addisonian crisis. requiring emergent administration of additional intravenous cortisol to avert a potential disaster. Within the next 5 days. but he remained on prednisone. Neuvonen M. and fluconazole is a strong 2C9 inhibitor and a moderate 3A4 inhibitor (Michalets and Williams 2000. 1999). Clin Pharmacokinet 40:723–751. with the result that the blood level of prednisone then precipitously declined. 2000 Niemi M. Clin Pharmacol Ther 69:194–200. Prednisone is a 3A4 substrate (Schwab and Klotz 2001). References Michalets EL. delirium. 2001). he experienced acute onset of fever. He was quickly given supplementary intravenous cortisol.134 Drug–Drug Interaction Primer INSUFFICIENCY A 42-year-old man had successfully undergone liver transplantation. When the fluconazole was discontinued. 3A4 returned to its baseline (higher) level of functioning. This led to a higher blood level of prednisone than would have existed had the fluconazole not been a part of the patient’s regimen. Clin Transplant 13:62–64. His fluconazole was eventually discontinued. This led to more efficient metabolism of prednisone by 3A4. abdominal pain. He was being maintained on tacrolimus (Prograf). He also was prescribed standing fluconazole (Diflucan) as a prophylactic antifungal agent. titrated to a level . vomiting. 2001 Schwab M. Clin Pharmacokinet 39:49–75. 2001 Tiao GM. Williams CR: Drug interactions with cisapride: clinical implications.

and he experienced it as helpful. When he had felt “blue” in the past. 2002). John’s wort. Br J Clin Pharmacol 53:75–82. which led to more tacrolimus being extruded from enterocytes back into the gut lumen. Armstrong. Spiers JP. 2002 Hennessy M. 2002). John’s wort. and St. et al: St Johns wort increases expression of P-glycoprotein: implications for drug interactions. and St. tenderness around the graft site.C. Thus. where it was excreted rather than absorbed. This led to a decrease in the blood level of tacrolimus. personal communication. and prednisone. who advised him to report to the nearest emergency room. Yunomae K. et al: Tacrolimus-induced nephrotoxicity unmasked by induction of the CYP3A4 system with St. Roby et al. John’s wort (letter). 1998). There was also a likely contribution to this decrease in the tacrolimus blood level from alterations in the functioning of the P-glycoprotein transporter. where he was admitted and a workup revealed that he was in the acute stage of organ rejection (S. and intermittent fevers. Roughly 1 month later. 2001 Bolley R. J Pharmacol Exp Ther 297:547–555. the patient developed oliguria. the St.Internal Medicine Case Vignettes 135 of roughly 14 ng/mL. He asked his wife to pick up some St. Tacrolimus is a P-glycoprotein substrate (Arima et al. even though there had been no decrease in the tacrolimus dosage (Bolley et al. May 2002). and he resumed taking this agent. He contacted his nephrologist. References Arima H. et al: Contribution of P-glycoprotein to the enhancing effects of dimethyl-beta-cyclodextrin on oral bioavailability of tacrolimus. This decreased tacrolimus blood level resulted in less effective immunosuppression. John’s wort is a P-glycoprotein inducer (Hennessy et al. which allowed the body’s immune system to reject the new kidney. 2000. he took St. more 3A4 was produced and thus available to metabolize the tacrolimus. Discussion This is an example of an inducer added to a substrate. John’s wort is a 3A4 inducer (Moore et al. John’s wort increased the activity of P-glycoprotein. Kammerl M. Kelleher D. With the addition of the St. 2001). 2002 . John’s wort at the supermarket pharmacy. Tacrolimus is a 3A4 substrate (Olyaei et al. Transplantation 73:1009. Zulke C. Hirayama F. He began to experience some depressive symptoms in the weeks after the operation. John’s wort (Hypericum perforatum). 2000). This increase in excretion and decrease in absorption of tacrolimus also contributed to the decrease in the tacrolimus blood level following the addition of St.

1997. roughly 3 years ago. the patient experienced increasing sedation. culminating in a syncopal episode that required a medical admission to rule out cardiac causes for his syncope. He consulted his internist. Clin Pharmacol Ther 67:451–457. 1991). Clin Pharmacol Ther 65:369–376. Nation et al. 1999 . 1998 Roby CA. 1990). Jones SA. 300 mg qid. Olesen and Linnet 2001). and syncope. had not required hospitalization since he was started on clozapine (Clozaril). the addition of cimetidine impaired the efficiency of all the P450 enzymes that play any significant role in the metabolism of clozapine. ataxia. 2D6. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Johansson I. However. 2000 SHORT-TERM GAINS A 42-year-old man with schizoaffective disorder. with a previously difficult clinical course. with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. 2C9. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. 300 mg qhs (blood level. 3A4. and CYP3A by H2-receptor antagonists. In the hospital. who prescribed cimetidine (Tagamet). in an effort to save the patient some money. Discussion This is an example of an inhibitor added to a substrate. Clozapine’s metabolism occurs primarily at 1A2. Norman DJ. et al: St. but his insurance plan co-pay for this medication climbed dramatically. and dizziness. within 5 days. He was taking pantoprazole (Protonix). 1997 Martinez C. Anderson GD. Goodwin B. orthostasis. This resulted in the patient’s sedation. et al: St. John’s wort: effect on CYP3A4 activity. CYP2D6. Albet C.552 ng/mL. Br J Clin Pharmacol 44:439–446. 1999. Thus. This decrease in the metabolism of clozapine led to a significant rise in the clozapine blood level (more than double in this case) (Szymanski et al. 2000 Olyaei AJ. Kantor E. Cimetidine is a “pan-inhibitor” of 1A2. deMattos AM. et al: Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2. his clozapine blood level was found to be 1. References Eiermann B. Proc Natl Acad Sci USA 97:7500–7502. Agundez JA. and 2C19 (Martinez et al.136 Drug–Drug Interaction Primer Moore LB. even though the clozapine dosage had not been changed. Engel G. et al: Interaction between tacrolimus and nefazodone in a stable renal transplant recipient. The enzymes 3A4 and 2C19 are also significant contributors. 691 ng/mL). Pharmacotherapy 18:1356–1359. 20 mg/day. for his reflux esophagitis.

Lieberman JA. He placed the patient on rifampin (in the form of Rifadin). 2C9. he remained unaware of this fact. part I. she was diagnosed with tuberculosis. although he was semiretired at the time. Zhou et al. Discussion This is an example of an inducer added to a substrate. the patient developed progressive cough. 1977). but she eventually required an admission to the inpatient unit after attempting to engage in inappropriate sexual activity with a male fellow patient on the front lawn of the day hospital. who resided in a nearby village. fatigue. in an effort to accommodate his important client(s). Clozapine’s metabolism occurs primarily at 1A2. Her affluent family insisted on taking her with them on an African safari. 1997. Olesen and Linnet 2001). 1995. 1985. because they were accustomed to downplaying their daughter’s mental illness. the patient was floridly psychotic and hypersexual. On several occasions she wandered off from their hotel. Over the next several weeks. Zilly et al. the addition of rifampin increased the . 2001 Szymanski S. Evans AM. Wietholtz et al. et al: A case-report of cimetidine-induced clozapine toxicity. Thus. 457 ng/mL). Within 1 month of starting rifampin. The enzymes 3A4 and 2C19 are also significant contributors. 3A4. 1990 Olesen OV. among other medications. Rifampin is a “pan-inducer” of 1A2. and 2C19 (Heimark et al. 1990. Her parents whisked her away. Clin Pharmacokinet 18:37–60. and intermittent fevers. 1991 VIP PSYCHOSIS (I) A 32-year-old woman with chronic paranoid schizophrenia was being stably maintained on clozapine (Clozaril). 1987. Her clozapine blood level was then discovered to be only 92 ng/mL. J Clin Psychiatry 52:21–22. with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. The parents did not spontaneously disclose that the patient was taking clozapine. 500 mg/day (blood level. despite the misgivings of her psychiatrist. She was initially admitted to a local day hospital. The parents insisted on taking the patient to the most prominent infectious disease specialist in the area. Picou D. Thus. and soon thereafter they all returned to the United States. chills. Strayhorn et al. and her family eventually discovered that she was engaged in a physically intimate relationship with one of the bellhops. Milne RW: Pharmacokinetic drug interactions with phenytoin. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. After an extensive workup. and the infectious disease specialist did not obtain as rigorous a history as was customary.Internal Medicine Case Vignettes 137 Nation RL. J Clin Pharmacol 41:823–832. Kay et al. 1997.

2002 Heimark LD. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. Br J Clin Pharmacol 44:439–446. References Breyer-Pfaff U. Breimer DD. Clin Pharmacol Ther 42:388–394. 1990 Zilly W. J Hepatol 22:78–81. Richter E: Stimulation of drug metabolism by rifampicin in patients with cirrhosis or cholestasis measured by increased hexobarbital and tolbutamide clearance.138 Drug–Drug Interaction Primer amount of 1A2. Drug Metab Dispos 29:1343–1348. Oertel R. Self TH: Update on rifampin drug interactions. 2001 Ebert U. 1977 . Frank UG. Thong NQ. et al: Effects of rifampin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. Kampmann JP. III. There was also a likely contribution from phase II glucuronidative metabolism. Br J Clin Pharmacol 30:471–475. Svendsen TL. even though the clozapine dosage had not been changed (Joos et al. 1987 Joos AA. 2000). Kaschka WP: Pharmacokinetic interaction of clozapine and rifampin in a forensic patient with an atypical mycobacterial infection. Johansson I. Baciewicz AM. Clozapine is a uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 substrate (Breyer-Pfaff and Wachsmuth 2001). Trager WF. J Clin Psychopharmacol 18:83–85. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine.to sixfold decreases in clozapine blood levels (Finch et al. Baciewicz AM. 2002). 3A4. Eur J Clin Pharmacol 56:299–304. J Clin Pharmacol 41:823–832. 1997 Wietholtz H. 2C9. 1985 Olesen OV. Zysset T. resulting in a sharp decline in the clozapine blood level. 2001 Strayhorn VA. et al: Induction of polymorphic 4′-hydroxylation of S-mephenytoin by rifampicin. 1998 Kay L. and rifampin is a UGT1A4 inducer (Ebert et al. et al: The mechanism of the warfarin–rifampin drug interaction. et al: The influence of rifampin treatment on caffeine clearance in healthy man. et al: Rifampin and rifabutin drug interactions: an update. Eur J Clin Pharmacol 11:287–293. Br J Clin Pharmacol 20:323–326. Marschall HU. Arch Intern Med 162:985–992. Arch Intern Med 157:2453–2458. Anthony LB. et al: Influence of rifampicin and isoniazid on the kinetics of phenytoin. Chrisman CR. 1995 Zhou HH. 1997 Finch CF. Gibaldi M. Engel G. 1998). Studies have demonstrated that the addition of rifampin to clozapine can produce three. and 2C19 that was available to metabolize the clozapine. Wachsmuth H: Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine. 2000 Eiermann B. Wood AJ. This interaction likely synergized with the extensive P450 interactions mentioned earlier.

However. she was transferred to the “best” facility in the country and eventually transitioned to the care of the “best” psychiatrist in her hometown for outpatient care. Ebert et al.” but they became concerned when she fell down several stairs in their home. Again. 2000).500 mg/day. and 2C19 (Heimark et al. 3A4. 2C9. 1985. Zilly et al. 1977). there was a breakdown in communications as to how and why she had come to require such an extraordinary dosage of clozapine. she experienced a grand mal seizure and was taken to the nearest emergency room. 1997. 1987. at which point she was requiring only every-other-week complete blood count (CBC) blood monitoring for neutropenia (per the monitoring guidelines at the time). producing an increase in the clozapine blood level. 3A4. clozapine’s metabolism occurs primarily at 1A2. where her clozapine blood level was found to be 1. with the discontinuation of the rifampin. However. 1990. and 2C19 and to maintain a therapeutic blood level in the face of this induction (Finch et al. on the way to have the blood drawn. She eventually completed the course of rifampin (Rifadin). Wietholtz et al. This led to a marked decrease in the efficiency with which these enzymes metabolized the clozapine. 2C9. The enzymes 3A4 and 2C19 are also significant contributors. 2002). the reversal of induction of glucuronidation enzyme 1A4 also contributed to this increase in the clozapine blood level (Breyer-Pfaff and Wachsmuth 2001. They contacted the psychiatrist. 1995. and 2C19 resumed their lower baseline levels of activity. The clozapine dosage had been increased to 2. she became severely sedated and ataxic. At first. 3A4. Had the lines of communication not been disrupted by the numerous elective transfers of care.500 mg/day to compensate for rifampin’s induction of 1A2. 1997. who advised them to watch her closely and he would order a clozapine blood level in addition to the planned CBC. Olesen and Linnet 2001). the psychiatrist would have tapered the clozapine . her family ascribed this to her being overly “dramatic. In the course of her treatment. which seemed like an immense dosage but only produced a blood level of 468 ng/mL. However. Her rifampin was discontinued just after one of her CBCs. Zhou et al. 2C9.853 ng/mL. Rifampin is a “pan-inducer” of 1A2. culminating in the patient’s toxicity symptoms and seizure. In the 2 weeks before her next CBC. 1A2. Kay et al. with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. Discussion This is an example of reversal of induction. in the midst of all these transitions. Again. Strayhorn et al.Internal Medicine Case Vignettes 139 VIP PSYCHOSIS (II) The patient in the previous case had her clozapine (Clozaril) dosage increased to 2.

700 mg/day (blood level. Clin Pharmacol Ther 42:388–394. et al: Induction of polymorphic 4′-hydroxylation of S-mephenytoin by rifampicin. 1995 Zhou HH. Oertel R. References Breyer-Pfaff U. he explained to her the importance of smoking cessation. she used a nicotine patch (prescribed by her internist) and abruptly stopped smoking. et al: Rifampin and rifabutin drug interactions: an update. and con- . Br J Clin Pharmacol 20:323–326. 2002 Heimark LD. During a routine checkup with her internist. Wachsmuth H: Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine. Eur J Clin Pharmacol 11:287–293. Br J Clin Pharmacol 30:471–475. Engel G. Svendsen TL. 1997 Finch CF. Johansson I. Baciewicz AM. especially in view of her moderate hypertension (even while on clozapine) and family history of early demise from cardiac events. 2000 Eiermann B. 2001 Ebert U. With the support and encouragement of her family and friends. Drug Metab Dispos 29:1343–1348. blurry vision. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Thong NQ. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. Richter E: Stimulation of drug metabolism by rifampicin in patients with cirrhosis or cholestasis measured by increased hexobarbital and tolbutamide clearance. Kampmann JP. 1985 Olesen OV. et al: The influence of rifampin treatment on caffeine clearance in healthy man. J Hepatol 22:78–81. she developed increasing sedation. Zysset T. Trager WF. Arch Intern Med 162:985–992. dizziness when rising from a sitting position. Within the next 3 weeks. et al: Effects of rifampin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. Gibaldi M. 1987 Kay L. Chrisman CR. Self TH: Update on rifampin drug interactions. 1997 Wietholtz H. Eur J Clin Pharmacol 56:299–304. et al: Influence of rifampicin and isoniazid on the kinetics of phenytoin. Breimer DD. Wood AJ. et al: The mechanism of the warfarin– rifampin drug interaction. 2001 Strayhorn VA. 1990 Zilly W. This would hopefully have avoided any acute increases in the clozapine blood level and accompanying complications. 1977 SMOKING GUN (II) A 47-year-old woman with chronic paranoid schizophrenia was being well maintained on clozapine (Clozaril). however. III. 455 ng/mL). Anthony LB. Br J Clin Pharmacol 44:439–446.140 Drug–Drug Interaction Primer back to the pre-rifampin baseline dosage (500 mg/day) in the weeks following discontinuation of the rifampin. J Clin Pharmacol 41:823–832. Baciewicz AM. Marschall HU. Arch Intern Med 157:2453–2458.

She reported her difficulties to her internist and psychiatrist. the “extra” 1A2 that had been induced by the tobacco died off over the following few weeks. and anticholinergic symptoms (blurry vision and constipation). After 4 days. References Eiermann B. The enzymes 3A4 and 2C19 are also significant contributors. Zullino et al. The clozapine blood level was 893 ng/mL. 1998. these two cases highlight the need to be prospectively aware of how changes. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. as the clozapine dosage would again have to be increased in order to prevent a decrease in clozapine blood levels and a subsequent loss of efficacy. is a significant 1A2 inducer (Schrenk et al. the psychiatrist prudently cautioned the patient to inform him if she resumed smoking. Olesen and Linnet 2001). 1997. and the psychiatrist ordered another clozapine blood level. 2002). sedation. Discussion This is an example of reversal of induction. even though the dosage had been constant until then (van der Weide et al. and the new plan was to dose the clozapine stably at 400 mg/day. 1997 . However. Engel G. Br J Clin Pharmacol 44:439–446. Because the metabolism of clozapine by 1A2 was now decreased. The previous clozapine dosage had been determined in the presence of constant tobacco use. in smoking behavior can affect drug metabolism in various ways. Her psychiatrist ordered an immediate clozapine blood level with instructions to then decrease her clozapine dosage to 400 mg/day for the time being. with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. 2003. which was now 485 ng/mL. the patient reported a remission of the aforementioned symptoms. via cigarette smoking. but he cautioned the patient that she needed to inform him as soon as possible if she resumed smoking. Clozapine’s metabolism occurs primarily at 1A2. Although smoking cessation is a laudable goal. Johansson I. Tobacco use. which caused a stable increase in the amount of 1A2 that was available to metabolize the clozapine. The psychiatrist successfully compensated for this reversal of induction by decreasing the clozapine dosage from 700 mg/day to 400 mg/day. The psychiatrist conferred with the patient. Zevin and Benowitz 1999). at which time these symptoms quickly remitted. resulting in a return to pre-smoking (lower) levels of 1A2 activity. When she stopped smoking. The resulting state of mild clozapine toxicity caused the patient to experience orthostasis. this led to an almost doubling of the patient’s clozapine blood level. This led to a rate of metabolism of clozapine that was significantly greater than if the patient had not been smoking. or briefly enforced differences.Internal Medicine Case Vignettes 141 stipation.

” By day 4 of his ciprofloxacin regimen. in addition to being our most commonly used psychoactive substance. Ilett KF. May 2002). Ciprofloxacin is a strong 1A2 inhibitor (Batty et al. Armstrong. he was experiencing frank jitteriness and palpitations. References Batty KT. He reported this to his internist. he was aware that his neuropathy might deaden the pain even if a serious infection was present. Following this discussion. Steijns LS. Clin Pharmacokinet 36:425–438. et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. personal communication. 1995). Although he felt no acute discomfort. Eur J Clin Pharmacol 53:361–367. J Clin Pharmacol 41:823–832. which caused his symptoms of agitation and palpitations. Br J Clin Pharmacol 39:305–311.C. Int Clin Psychopharmacol 17:141–143. 1996). is a 1A2 substrate (Miners and Birkett 1996). Delessert D. Cozza. The addition of the ciprofloxacin markedly impaired the ability of 1A2 to efficiently metabolize caffeine (Mizuki et al. who diagnosed cellulitis and prescribed ciprofloxacin (Cipro). Morike K. van Weelden MJ: The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Discussion This is an example of an inhibitor added to a substrate. Pharmacogenetics 13:169–172.to threefold) in the blood level of caffeine following the patient’s usual consumption of two cups of coffee.142 Drug–Drug Interaction Primer Olesen OV. et al: Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Benowitz NL: Drug interactions with tobacco smoking: an update. 2003 Zevin S. This led to a marked increase (often two. S.L. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. 1998 van der Weide J. et al: The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects. Caffeine. 2001 Schrenk D. who consulted his affiliated hospital’s pharmacist. the internist instructed the patient to drink decaffeinated coffee and avoid other caffeinated beverages for the duration of the ciprofloxacin treatment course (K. The patient had long relied on two strong cups of coffee to help him “start the day. 1999 Zullino DF. 1995 . Davis TM. Eap CB. Brockmeier D. 2002 JAVA JITTERS A 55-year-old man with diabetes noticed that a sore on the underside of his right foot was growing in size and becoming more red and warm. He therefore visited his internist.

although her cough did begin to clear. 1996 ANXIOUS ABOUT ANTHRAX A 27-year-old woman with chronic paranoid schizophrenia had been maintaining a reasonable degree of clinical stability while taking clozapine (Clozaril). the ability of 1A2 and 3A4 to significantly contribute to the metabolism of clozapine was markedly impaired. 1995. She convinced her internist to prescribe a course of ciprofloxacin (Cipro). 410 ng/mL). even though the clozapine dosage had not been changed (Raaska and Neuvonen 2000). The resulting state of mild clozapine toxicity explained the patient’s emerging somatic symptoms. Over the course of 1 week. 1997. whereupon she became convinced that she had contracted anthrax. She finally called an ambulance to transport her to the nearest emergency room. and sedation were attributable to her mild clozapine toxicity. although some chronic paranoia was generally present. Davis TM. she became progressively weaker. dizziness. Birkett DJ: The use of caffeine as a metabolic probe for human drug metabolizing enzymes. 600 mg/day (blood level. Gen Pharmacol 27:245–249. more sedated. McLellan et al. Ciprofloxacin is a strong inhibitor of both 1A2 and 3A4 (Batty et al. Enzymes 3A4 and 2C19 are also significant contributors. she developed a persistent cough and low-grade fever. Yamaguchi T: Pharmacokinetic interactions related to the chemical structures of fluoroquinolones. Fujiwara I. The emergency room physician was able to reassure her that she did not have anthrax and that her weakness. Ilett KF. their inhibition led to an almost doubling of the clozapine blood level. Br J Clin Pharmacol 39:305–311. Within 5 days. Nonetheless. because her blood level had risen to 734 ng/mL. and dizzy. J Antimicrob Chemother 37(suppl):41– 55. she was convinced that she had not begun the ciprofloxacin early enough and that these new symptoms were the result of infection with anthrax. Clozapine’s metabolism occurs primarily at 1A2. 1996 Mizuki Y. et al: The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects. 1995 . References Batty KT. 1996). Discussion This is an example of an inhibitor added to a substrate. with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. With the addition of the ciprofloxacin. Because these two enzymes handle the majority of clozapine’s metabolism. Olesen and Linnet 2001).Internal Medicine Case Vignettes 143 Miners JO.

2D6. Drug Metab Dispos 24:1134–1138. Discussion This is an example of an inhibitor added to a substrate. the blood level of olanzapine rose. even though there had been no increase in the olanzapine dosage. The psychiatrist compensated for the decreased metabolism of olanzapine by decreasing the dosage from 25 mg/day to 15 mg/day. 2000 GI JOE A 27-year-old man with chronic paranoid schizophrenia was being stably maintained on olanzapine (Zyprexa). Monshouwer M. Olanzapine is a 1A2 substrate. Cimetidine is a “paninhibitor” that strongly inhibits 1A2. he decreased the dosage of olanzapine to 15 mg/day. 2001 Raaska K. He developed some persistent heartburn. 1A2 and 2D6 were impaired in their ability to contribute to olanzapine’s metabolism. et al: Fluoroquinolone antibiotics inhibit cytochrome P450–mediated microsomal drug metabolism in rat and human. he was diagnosed with gastroesophageal reflux disease. With the addition of the cimetidine. for cost reasons. When his psychiatrist was consulted. Eur J Clin Pharmacol 56:585– 589. Engel G. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. Ptak LR. Clin Pharmacokinet 37:177–193. which led to the emergence of olanzapine side effects (sedation and constipation) (Pies 2002). After 5 days. although it is also metabolized by 2D6 and phase II glucuronidation (Callaghan et al. which led him to visit his primary care physician. J Clin Pharmacol 41:823–832.144 Drug–Drug Interaction Primer Eiermann B. which promptly led to a remission of these symptoms. The patient remained psychiatrically stable throughout and into the future. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. 25 mg/day. 1999). Thus. 1999 . Br J Clin Pharmacol 44:439–446. although the majority of this inhibition likely occurred at 1A2. 1997 McLellan RA. Bergstrom RF. the patient experienced increased sedation and constipation. 1996 Olesen OV. After a gastrointestinal workup. and 3A4 (Martinez et al. 300 mg qid. et al: Olanzapine: pharmacokinetic and pharmacodynamic profile. which led to a remission of these side effects with a preservation of antipsychotic efficacy. References Callaghan JT. Drobitch RK. Johansson I. 1999). and his doctor prescribed cimetidine (Tagamet). Neuvonen PJ: Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia.

Smoking significantly induces the production of 1A2 (Schrenk et al. thus increasing the efficiency with which cyclobenzaprine is metabolized by 1A2 and lowering cyclobenzaprine blood levels.L. he felt increasingly lethargic and fatigued. S. Zevin and Benowitz 1999). The patient followed his instructions. He initially attributed this to his body “getting used to exercise. CYP2D6. 15 mg tid. over the next 2 weeks. the dosages required to maintain a therapeutic blood level of cyclobenzaprine were therefore higher than those needed had he not been smoking. When he stopped smoking. He eventually contacted his internist. then resume at a dose of 10 mg tid. and he reported no further difficulties after that (K. 1996). Discussion This is an example of reversal of induction. When the internist learned about the patient’s new fitness program and that he had recently stopped smoking. 1999 Pies R: Cytochromes and beyond: drug interactions in psychiatry. who asked about any recent life changes. et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. he felt better and proceeded with his new exercise and diet programs. Cyclobenzaprine is a substrate of 1A2 and 3A4 (Wang et al. After a difficult 2–3 days. May 2002). May 2002. pp 48–51 SMOKING GUN (III) A 52-year-old man with multiple musculoskeletal complaints was being chronically maintained on cyclobenzaprine (Flexeril). Psychiatric Times. Clin Pharmacol Ther 65:369–376. 1998. This likely led to an increase in the cyclobenzaprine blood level. Albet C.C. et al: Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2. Agundez JA. 1998 . personal communication.” but the feeling of being sedated did not remit even when he abstained from exercise for 3 days. with resulting sedation and lethargy. Brockmeier D. and CYP3A by H2-receptor antagonists. Cozza. His internist compensated for this reversal of 1A2’s induction by decreasing the dosage of cyclobenzaprine. even though the dosage had not been increased. However. 1A2 returned to its lower baseline level of activity.Internal Medicine Case Vignettes 145 Martinez C. which included cessation of smoking. Eur J Clin Pharmacol 53:361–367. References Schrenk D. leading to a remission of these symptoms. While the patient was smoking. He decided to adopt a healthier lifestyle. He went “cold turkey” and abruptly stopped smoking. Armstrong. he told the patient to stop taking the cyclobenzaprine for 1 day. Morike K.

this problem was quickly identified and remedied by increasing the clozapine dosage to 600 mg/day. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Once the patient was in the hospital. 1991). 1997 . Olesen and Linnet 2001). 1997. Clin Pharmacokinet 36:425–438. This decreased clozapine level led to a recurrence of psychotic symptoms. with the discontinuation of the cimetidine. 391 ng/mL). Cimetidine is a pan-inhibitor of 1A2. 1999 NEW AND IMPROVED A 37-year-old woman with chronic paranoid schizophrenia was being maintained on clozapine (Clozaril). Liu L. 2D6. even though the dosage had not changed throughout. 3A4. Enzymes 3A4 and 2C19 are also significant contributors. from her primary care physician for persistent indigestion. Drug Metab Dispos 24:786–791. 1990). 1999. Nation et al. 2C9. Br J Clin Pharmacol 44:439–446. The patient was also receiving cimetidine (Tagamet). Benowitz NL: Drug interactions with tobacco smoking: an update.146 Drug–Drug Interaction Primer Wang RW. she was experiencing an increase in her paranoid and somatic delusions and auditory hallucinations telling her that she was the daughter of Satan. Clozapine’s metabolism occurs primarily at 1A2. Engel G. Cheng H: Identification of human liver cytochrome P450 isoforms involved in the in vitro metabolism of cyclobenzaprine. which led to more efficient metabolism of the clozapine and a significant decrease in the clozapine blood level. She consented to a hospital admission. Discussion This is an example of reversal of inhibition. all these enzymes resumed their higher baseline levels of activity. 300 mg/day (blood level. with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. References Eiermann B. 1996 Zevin S. Her subsequent blood level was 425 ng/mL. Johansson I. stating that this was a “new and improved” version of the cimetidine. Thus. Within 3 weeks. A clozapine blood level in the hospital was only 136 ng/mL. 300 mg qid. During a routine visit to her primary care physician. and 2C19 (Martinez et al. the presence of cimetidine impaired the efficiency of all the P450 enzymes that play any significant role in the metabolism of clozapine and led to a higher blood level of clozapine than would have occurred had the cimetidine not been present (Szymanski et al. he discontinued her cimetidine and started her on pantoprazole (Protonix). Thus.

this led to an increase in the blood level of phenytoin and the patient’s signs of phenytoin toxicity (Blum et al. 2001 Szymanski S. but her current phenytoin blood level was 32. she was pervasively groggy. 1998). Picou D. 1994. CYP2D6. J Clin Pharmacol 41:823–832. She was taking 300 mg/day. Clin Pharmacol Ther 65:369–376. The physician asked her if she was taking any medications at present. her coach arranged for her to be taken to the nearest emergency room. Because 2C19 was not able to compensate for the inhibition of 2C9. the physician thought she was taking this medication as a way of maintaining her high fitness level. Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. She visited a physician in the host city because she was troubled by increasingly unpleasant vaginal itching and burning. 1999 Nation RL. Clin Pharmacokinet 18:37–60. 200 mg on day 1 and 100 mg/day for 2 weeks thereafter. J Clin Psychiatry 52:21–22. 2001). Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. 1991). Lieberman JA. and slurring her speech. 1990 Olesen OV. 1991 DOUBLE FAULT A 23-year-old professional tennis player from South Africa was visiting the United States in order to play in a tennis tournament.Internal Medicine Case Vignettes 147 Martinez C. uncoordinated. Thus. Discussion This is an example of an inhibitor added to a substrate. the addition of the fluconazole significantly impaired the ability of 2C9 to contribute to the metabolism of phenytoin. Mamiya et al. Albet C.8 µg/mL. Agundez JA. et al: Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2. and fluconazole is a strong 2C9 inhibitor (Niemi et al. Evans AM. . however.” Because of her accent. nauseated. part I. After determining that she had not just returned from a drinking binge. He also brought her medication bottles with them so that the emergency room physician was able to learn that Epanutin was phenytoin (Dilantin in the United States). et al: A case report of cimetidine-induced clozapine toxicity. and the physician prescribed fluconazole (Diflucan). and CYP3A by H2-receptor antagonists. She replied that she took a medication called Epanutin because she sometimes had “fits. Milne RW: Pharmacokinetic drug interactions with phenytoin. By day 5 of the fluconazole. She was eventually diagnosed with vaginal candidiasis.

the addition of omeprazole significantly impaired the ability of 2C19 to contribute to the efficient metabolism of phenytoin. 1998 Niemi M. The enzyme 2C9 was not able to fully compensate for this 2C19 inhibition. 2001 FROM HEARTBREAK TO HEARTBURN A 58-year-old widower had been chronically taking phenytoin (Dilantin). especially in the late evenings. so that the inhibition . Zenon GJ 3rd. 1998). et al: The effects of genetic polymorphism of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics.1 µg/mL. he was frankly unsteady on his feet and felt drunk.148 Drug–Drug Interaction Primer References Blum RA. 300 mg bid. He had recently broken up with a woman he had been dating for 18 months. He eventually made an appointment with his internist.9 µg/mL. and omeprazole is a strong inhibitor of 2C19. Mamiya et al. the patient began to experience increased sedation and a sensation of being less mentally acute. After 1 week on the omeprazole. Nousbaum et al. Ann Pharmacother 28:191–195. 1994). who prescribed omeprazole (Prilosec). Discussion This is a mixed example of a P450 inhibitor (omeprazole) added to a substrate (phenytoin) and a P-glycoprotein inhibitor (omeprazole) added to a P-glycoprotein substrate (phenytoin). et al: Fluconazole-induced symptomatic phenytoin toxicity. Neuvonen M. 40 mg/day. Rodriguez-Barradas MC. phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. First. Thus. Hilligoss DM. et al: Effect of fluconazole on the disposition of phenytoin. 2001. 1994. Clin Pharmacol Ther 49:420–425. 1994 Mamiya K. where his phenytoin blood level was found to be 27. he also experienced a worsening of heartburn pain. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Shimamoto J. His most recent phenytoin blood level was 16. Clin Pharmacol Ther 69:194–200. The neurologist told him to call 911 for an ambulance to transport him to the nearest emergency room. Within several days. for a seizure disorder. In addition to gaining several pounds. Ieiri I. He coped with this loss by increasing his food intake. 1991 Cadle RM. as well as an inducer of 1A2 (Furuta et al. He contacted his neurologist and informed him of his current symptoms as well as of the fact that he was now taking omeprazole. Backman JT. and he was quite demoralized in the wake of the breakup. which he had felt off and on for the past 5 years. Wilton JH. Epilepsia 39:1317–1323.

Br J Clin Pharmacol 24:453–455. Am J Ther 7:359–363. 2001 Prichard PJ. so that an increased amount was absorbed. Am J Gastroenterol 89:371–375. and omeprazole is a P-glycoprotein inhibitor (Pauli-Magnus et al. Part of the increase in the phenytoin was likely attributable to the fact that phenytoin is a P-glycoprotein substrate (Weiss et al. ultimately resulting in an increase in the blood level of phenytoin. the inhibition of the P-glycoprotein transporter allowed more phenytoin to remain in enterocytes. Scand J Gastroenterol Suppl 108:79–94. Walt RP. Naunyn Schmiedebergs Arch Pharmacol 364:551–557. Berthou F. et al: The effects of genetic polymorphism of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. Suzuki T. Rekersbrink S. et al: Fluconazole-induced symptomatic phenytoin toxicity. Pharmacogenetics 1:157–158. References Cadle RM. 1987 Regardh CG. Carlhant D. such that phenytoin was less likely to be extruded from enterocytes back into the gut lumen. 2001). Jensen JC: Omeprazole inhibits oxidative drug metabolism: studies with diazepam and phenytoin in vivo and 7-ethoxycoumarin in vitro. Kodama Y. Hoffman KJ. Shimamoto J. Palmer LJ: Case-control association studies in pharmacogenetics. 1998 Nousbaum JB. cimetidine and omeprazole. et al: Four-week treatment with omeprazole increases the metabolism of caffeine. Epilepsia 39:1317–1323. Klotz U.Internal Medicine Case Vignettes 149 of 2C19 by omeprazole caused the phenytoin blood level to rise into the toxic range. 2000 Mamiya K. 1985 Kodama H. Zenon GJ 3rd. Prichard et al. Shinozawa S. 1987). 1994 Furuta S. the addition of the omeprazole inhibited the functioning of this transporter. et al: In vivo binding characteristics of phenytoin to serum proteins in monotherapy for adults with epilepsy. where it would have been excreted rather than absorbed. Silverman EK. 1994 Pauli-Magnus C. Rodriguez-Barradas MC. et al: Interaction of omeprazole. Ann Pharmacother 28:191–195. 1985 Weiss ST. Kamada E. et al: Pharmacokinetics and metabolism of omeprazole in animals and man: an overview. 2001 Gugler R. Gastroenterology 89:1235–1241. 2001). 2001 . resulting in symptoms of clinical phenytoin toxicity (Gugler and Jensen 1985. Kitchingman GK. Xenobiotica 31:1–10. et al: Oral phenytoin pharmacokinetics during omeprazole therapy. Thus. et al: Inhibition of drug metabolism in human liver microsomes by nizatidine. Ieiri I. Instead. Gabrielsson M. lansoprazole and pantoprazole with P-glycoprotein.

Thus. Rodriguez-Barradas MC. even though there had been no increase in the dosage of phenytoin (Tse et al. 1998 Tse CS. 1993). He began to develop chronic indigestion pain. 400 mg/day (blood level. and his symptoms remitted within 2 days of doing so. 1988 Cadle RM. which was 21. These symptoms became so severe that he cancelled his workday for fear that he would hurt a patient by slipping during a procedure. and he made an appointment with his internist to address this complaint. who instructed the patient to report to the local emergency room for a stat phenytoin blood level. et al: Fluconazole-induced symptomatic phenytoin toxicity. Shimamoto J. 1994 Mamiya K. Epilepsia 39:1317–1323. Ranitidine is considered to pose minimal risks for drug interactions. Ieiri I. Over the course of the next week. Ann Pharmacother 27:1448–1451. Akinwande KI. individual cases have demonstrated that the addition of ranitidine to phenytoin can increase phenytoin blood levels by roughly 40% (Bramhall and Levine 1988). He contacted his internist. 1993). Ann Pharmacother 28:191–195. Discussion This is an example of an inhibitor added to a substrate. 1998). However. difficulty concentrating. Drug Intell Clin Pharm 22:979–980. generally 13–15 µg/mL) for 25 years to treat his seizure disorder. Levine M: Possible interaction of ranitidine with phenytoin. 1994. Mamiya et al. His internist prescribed ranitidine (Zantac). Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. 1993 .8 µg/mL. Biallowons K: Phenytoin concentration elevation subsequent to ranitidine administration. the addition of ranitidine led to an impairment in the ability of 2C9 and 2C19 to contribute to the metabolism of phenytoin.150 Drug–Drug Interaction Primer THE DIZZY DENTIST A 63-year-old dentist had been taking phenytoin (Dilantin). and ranitidine is (probably) a mild to moderate inhibitor of both 2C9 and 2C19 (Bramhall and Levine 1988. et al: The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. Tse et al. This inhibition caused the blood level of phenytoin to increase. 150 mg bid. the patient experienced increasing dizziness. It is certainly much less generally a culprit than the pan-inhibitor cimetidine (Tagamet). His internist instructed him to immediately stop his ranitidine. Zenon GJ 3rd. and tremor. References Bramhall D.

R-warfarin does produce some direct anticoagulant effect. the patient accidentally. but lightly. even though the dosage of warfarin had remained constant throughout (Yap and Low 1999).0 for another 10 days.4). 2002. Fluvoxamine is a strong inhibitor of 1A2. 1991). 1987. she experienced a recurrence of her major depressive disorder. These combined influences caused a significant increase in the patient’s INR. and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. Niemi et al. First. Linder and Valdes 1999). The more active S-warfarin isomer is metabolized primarily by P450 2C9 (Heimark et al. 5 mg/day (international normalized ratio [INR]. Second.8. fluvoxamine’s inhibition of 1A2 and 3A4 yielded an increase in R-warfarin. 2C9. von Moltke et al. The fluvoxamine was immediately discontinued. . She informed her internist about this. After 3 weeks in the hospital. Third. bumped her arm on the side rail of her hospital bed. Warfarin’s metabolism is very complex. titrating the medication upward to a dosage of 100 mg/day. The addition of fluvoxamine led to an increase in the INR through several mechanisms. Thus. an increase in R-warfarin levels led to more inhibition of the metabolism of S-warfarin.Internal Medicine Case Vignettes 151 BRUISER A 75-year-old woman with a history of previous major depressive episodes (no treatment for years) was hospitalized on the medical floor following a pulmonary embolus due to formation of a deep venous thrombosis in her right thigh. She was surprised that she immediately developed a large and ugly bruise on her arm as a result. fluvoxamine significantly impaired the ability of 2C9 to metabolize the S-warfarin. 2. to almost 2½ times the baseline value. The less active R-warfarin isomer is metabolized primarily at 1A2 (Lehmann 2000). and he ordered a stat prothrombin time. After 1 week of taking this dosage of fluvoxamine. Her internist prescribed fluvoxamine (Luvox). 2001. The internist eventually had to administer vitamin K to address her persistently high INR. yielding higher S-warfarin levels. which placed the patient in a pathologically hypocoagulable state in which she bruised very easily and was in danger of vascular hemorrhage. but her INR did not fall below 3. She was initially treated with intravenous heparin and then transitioned to warfarin (Coumadin). Although it is a less potent anticoagulant than S-warfarin. which revealed an INR of 5. R-warfarin is itself an inhibitor of P450 2C9 (Kunze et al. Discussion This is an example of an inhibitor added to a substrate. leading to an increase in the blood level of this warfarin isomer. 1995).

where he was diagnosed with acute acetaminophen-induced hepatitis (K. Valdes R Jr: Pharmacogenetics in the practice of laboratory medicine. He attempted to “nuke” this headache by taking a bolus of 3. 1999 Niemi M. Eddy AC. et al: Metabolic enantiomeric interactions: the inhibition of human (S)-warfarin-7-hydroxylase by (R)-warfarin. J Clin Psychopharmacol 15:125–131. Clin Pharmacol Ther 71:141–152. such that he experienced a severe vascular headache. he did not enter florid delirium tremens. Mol Diagn 4:365–379. May 2002). 2001 von Moltke LL. The brother drove the patient to the nearest emergency room. Trager WF. Mihara K. and pain under his ribs on the right side. Tybring G. just after the inducer had been discontinued.C. After another 2 days. . 1999 ALL THINGS IN EXCESS A 23-year-old man with alcohol dependence discontinued his alcohol intake as a prerequisite for moving in with his brother. Cozza. 1987 Kunze KL. Clin Pharmacol Ther 69:194–200. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. 2000 Linder MW. Gibaldi M. 1991 Lehmann DE: Enzymatic shunting: resolving the acetaminophen-warfarin controversy. et al: The mechanism of the warfarin– rifampin drug interaction. His brother also noted that his skin had a yellowish tint. Clin Pharmacol Ther 42:388–394. Discussion This is an example of a substrate added to an induced enzyme. Court MH. Armstrong. personal communication.152 Drug–Drug Interaction Primer References Christensen M. vomiting. Backman JT.250 mg of acetaminophen (Tylenol). 1995 Yap KB. Singapore Med J 40:480–482. had no appetite. After 2 days of abstinence. 2002 Heimark LD. Greenblatt DJ. Neuvonen M. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). S.L. Pharmacotherapy 20:1464–1468. and was experiencing nausea. Low ST: Interaction of fluvoxamine with warfarin in an elderly woman. but he did have a moderate degree of tachycardia and hypertension. he told his brother that he was feeling weak. Chirality 3:24–29. Gibaldi M.

et al: Duration of cytochrome P-450 2E1 (CYP2E1) inhibition and estimation of functional CYP2E1 enzyme half-life after single-dose disulfiram administration in humans. 1999 Kharasch ED. Because her internist was both unfamiliar with and uncomfortable with bupropion. However. Thummel KE. Horsmans Y: Inhibition of chlorzoxazone metabolism. 1992 TOO MUCH OF A GOOD THING (I) A 66-year-old woman with previously diagnosed dysthymic disorder and significant coronary artery disease had been maintained on bupropion (Wellbutrin). Jubert C. a clinical probe for CYP2E1. Csomos G: Alcohol and the liver: ethanol metabolism and the pathomechanism of alcoholic liver damage (in Hungarian). Jubert C. by a single ingestion of watercress. when the patient took the large bolus of acetaminophen. he discontinued the bupropion and started the patient on fluoxe- . there was a greater than normal amount of 2E1 that was available to metabolize acetaminophen down this specific metabolic pathway. of 2E1. Conventional treatment at this point would involve the administration of N-acetylcysteine (Mucomyst) to promote glutathione synthesis and thus neutralize this toxic metabolite.Internal Medicine Case Vignettes 153 Acetaminophen is a substrate of 2E1 (Manyike et al. Drug Metab Dispos 27:717–723. this excessive metabolism of acetaminophen by 2E1 led to the accumulation of a hepatotoxic metabolite. Thus. such as disulfiram (Antabuse) (Emery et al. Quinidine (Quinaglute) was one of her cardiac medications. and thus decrease the generation of the NAPQI metabolite. the metabolism of acetaminophen was “dragged” down the 2E1-mediated pathway to a greater than normal degree. N-acetyl-p-benzoquinone imine. and 3A4 activities: evidence for specificity toward P-450 2E1. and thus activity. J Pharmacol Exp Ther 291:213–219. and chronic alcohol consumption is a potent inducer of 2E1 (Seitz and Csomos 1992). 2000). A less conventional. 1999) or watercress (Leclercq et al. Kalhorn TF. Hankins DC. Kharasch et al. 1998 Manyike PT. 2C19. or NAPQI (Manyike et al. et al: Lack of single-dose disulfiram effects on cytochrome P-450 2C9. 2000). but likely helpful. Kharasch ED. 1999. Clin Pharmacol Ther 64:144–149. 1999 Leclercq I. In effect. Orv Hetil 133:3183–3189. by virtue of the greater availability. Clin Pharmacol Ther 67(3): 275–282. 1998). Desager JP. approach would be to also administer a 2E1 inhibitor. 2D6. References Emery MG. 2000 Seitz HK. et al: Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation.

20 mg/day. Thus. irritability. Although this seems reasonable. unfortunately no quinidine levels were drawn to verify this conjecture. among other P450 enzymes (Greenblatt et al. norfluoxetine) is a strong 2D6 inhibitor and a moderate inhibitor of 3A4 (Greenblatt et al. the quinidine impaired the ability of 2D6 to make a significant contribution to the metabolism of fluoxetine. et al: CO binding kinetics of human cytochrome P450 3A4: specific interaction of substrates with kinetically distinguishable conformers. Discussion This case is a combined example of an inhibitor (quinidine) added to a substrate (fluoxetine) and a substrate (quinidine) added to an inhibitor (fluoxetine). self-report. 1999. Robinson RC.154 Drug–Drug Interaction Primer tine (Prozac). Harmatz JS. even though the fluoxetine dosage had not been changed. Buters JT. and fluoxetine. quinidine is a 3A4 substrate (Koley et al. References Greenblatt DJ. This very serious and potentially lethal syndrome is characterized by a systemic excess of serotonergic activity. At 20 mg/day. and fluoxetine (in concert with its active metabolite. This elevation in the fluoxetine blood level was sufficient to produce a central serotonin syndrome in this case. the fluoxetine was being given at a dosage that would be appropriate for antidepressant action. However. Stevens and Wrighton 1993). 2001). is a substrate of 2D6. J Biol Chem 270:5014–5018. metabolism. 1994). the fluoxetine impaired the ability of 3A4 to efficiently metabolize the quinidine. October 1995). et al: Human cytochromes and some newer antidepressants: kinetics. diarrhea. myoclonus. flushing. quinidine is one of the most potent 2D6 inhibitors in existence (von Moltke et al.B. First. the patient developed a progressive syndrome characterized by severe agitation. likely resulting in an increase in the blood level of quinidine. and drug interactions. The visual hallucinations in this case likely represent a state of quinidine toxicity superimposed on the aforementioned central serotonin syndrome. Sandson. von Moltke LL. Ring et al. 1995 . 1999. Over the next 1–2 weeks. 1995). Second. J Clin Psychopharmacol 19(suppl):23S–35S. which led to an increase in the blood level of fluoxetine. a selective serotonin reuptake inhibitor. intermittent disorientation to place and time. 1999 Koley AP. and visual hallucinations of little men playing musical instruments at the foot of her bed without an auditory component (N. even though the quinidine dosage had not been changed.

Discussion This is an example (actually two examples) of a substrate added to an inhibitor. Cimetidine is a potent inhibitor of 2D6. This escalation of the paroxetine blood level caused excessive inhibition of serotonin reuptake. 2001 Stevens JC. Within 5 days. and with antipyretics. 1995). insomnia. and by quinidine and ketoconazole: a model system to predict drug interactions in vivo. breaking and entering. 2D6 was severely impaired in its ability to metabolize the paroxetine.Internal Medicine Case Vignettes 155 Ring BJ. muscle relaxants. and he added paroxetine (Paxil). Quinidine is both a substrate of 3A4 and an extremely potent 2D6 inhibitor (Koley et al. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. and vomiting. his cimetidine and paroxetine were discontinued. to the patient’s regimen. and he had a recurrence of his depression following the news that his son had been placed in jail on charges of drug possession. Eckstein JA. He was promptly hospitalized. et al: Identification of the human cytochromes p450 responsible for in vitro formation of R. myoclonus. 3A4. 1995. His cardiologist opted to start him on quinidine (Quinaglute). fever. and it is a potent 2D6 inhibitor (von Moltke et al. et al: Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants. When the paroxetine was added to the cimetidine and quinidine. Gillespie JS. . the patient was experiencing a full central serotonin syndrome. with flushing. titrating the quinidine dosage purely according to quinidine blood levels until a therapeutic dosage (lower than a typical quinidine dosage. 1993 von Moltke LL. Cotreau-Bibbo MM. which led to a significant increase in the blood level of paroxetine. 1994). von Moltke et al. 1994 TOO MUCH OF A GOOD THING (II) A 49-year-old man was being treated with cimetidine (Tagamet). Paroxetine is metabolized principally by 2D6 (GlaxoSmithKline 2001). 20 mg/day. J Pharmacol Exp Ther 266:964–971. 300 mg qid. His internist noted his dysphoria. J Pharmacol Exp Ther 297:1044–1050. and 1A2 (Martinez et al. delirium. for reflux esophagitis when he developed a cardiac arrhythmia. and liberal quantities of lorazepam (Ativan). This patient also had a remote history of major depressive disorder. and aggravated assault. Greenblatt DJ. leading to the central serotonin syndrome. in this case) and level were achieved. he made a full recovery in another 5 days (Pies 2002). J Pharmacol Exp Ther 268:1278–1283.and S-norfluoxetine. 1999). and anhedonia.

who decided to discontinue the cimetidine and . Second. Psychiatric Times. doxepin (Sinequan). Clin Pharmacol Ther 65:369–376. Court MH. Agundez JA. 1999 Pies R: Cytochromes and beyond: drug interactions in psychiatry. et al: Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2. 25 mg/day (blood level generally around 250 ng/mL). May 2002. Greenblatt DJ. which automatically took cimetidine’s 3A4 inhibition of quinidine’s metabolism into account. The reasons are twofold. and by quinidine and ketoconazole: a model system to predict drug interactions in vivo. et al: Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants. fluoxetine is a moderate inhibitor of 3A4. and she experienced more heartburn in the evenings. and thus generate increased quinidine blood levels. 1995 DANGEROUS DISINHIBITION A 35-year-old woman with severe. fluoxetine was more able to impair the metabolism of quinidine at 3A4. CYP2D6. Thus. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. 1995 Martinez C. Buters JT. She consulted with her gastroenterologist. References GlaxoSmithKline: Paxil (package insert). Greenblatt DJ. Robinson RC. et al: CO binding kinetics of human cytochrome P450 3A4: specific interaction of substrates with kinetically distinguishable conformers. 300 mg qid. the shrewd decision was made to titrate the quinidine dosage according to blood levels. as there was in the previous case (“Too Much of a Good Thing [I]”). 1994 von Moltke LL. Her depression had not previously responded to antidepressant monotherapy with fluoxetine. J Pharmacol Exp Ther 268:1278–1283. and cimetidine (Tagamet). 60 mg/day. when fluoxetine was added to quinidine. Cotreau-Bibbo MM. NC. than was paroxetine. 2001 Koley AP. whereas paroxetine’s 3A4 inhibition is much weaker. First. Research Triangle Park.156 Drug–Drug Interaction Primer It is worth noting that there was not a superimposed element of quinidine toxicity. J Biol Chem 270:5014–5018. Her GERD began to worsen. and CYP3A by H2-receptor antagonists. GlaxoSmithKline. rather than to titrate quinidine according to preset dosing guidelines—a dosing strategy that would likely have led to a state of quinidine toxicity. pp 48–51 von Moltke LL. J Clin Psychopharmacol 15:125–131. 60 mg/day. Albet C. recurrent major depression and chronic gastroesophageal reflux disease (GERD) had been reasonably stable on the following regimen: fluoxetine (Prozac).

References Greenblatt DJ. J Clin Psychopharmacol 19(suppl):23S–35S. Psychiatric Times. 7-ethoxycoumarin. 1999 . was dependent on the presence of robust inhibitors of its metabolism. norfluoxetine) is a strong 2D6 inhibitor and a moderate 3A4 inhibitor (Greenblatt et al. at this dosage. Krausz KW. et al: Eight inhibitory monoclonal antibodies define the role of individual P450s in human liver microsomal diazepam. but this blood level was not sufficient to prevent a relapse of depression. and 1A2 in a manner similar to that of imipramine (Yang et al. 1993 Yang TJ. and fluoxetine (in concert with its active metabolite. J Pharmacol Exp Ther 266:964–971. Harmatz JS. metabolism. and 1A2 to metabolize the doxepin. Wrighton SA: Interaction of enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. Pies 2002). 2C19. she became desperately depressed and required psychiatric hospitalization after an overdose attempt. Stevens and Wrighton 1993). Doxepin is a tertiary-amine tricyclic antidepressant whose metabolism depends most on the intact functioning of 2C19. and imipramine metabolism. with a resulting decrease in the doxepin blood level. Cimetidine is a potent pan-inhibitor of all major P450 enzymes except for 2E1 (Martinez et al. et al: Human cytochromes and some newer antidepressants: kinetics. Drug Metab Dispos 27:102–109. Discussion This is an example of reversal of inhibition. Thus. even though the dosage had not been changed. pp 48–51 Stevens JC. et al: Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2. 1999). Clin Pharmacol Ther 65:369–376. von Moltke LL. 1999 Martinez C. Benedek. 3A4. and CYP3A by H2-receptor antagonists. 1999 Pies R: Cytochromes and beyond: drug interactions in psychiatry. Albet C. Sai Y. 2D6. The discontinuation of the cimetidine led to decreased inhibition of the ability of 2D6.Internal Medicine Case Vignettes 157 instead have her start taking pantoprazole (Protonix). and drug interactions. 3A4. Within 5 weeks. The continuing 2D6 and 3A4 inhibition provided by fluoxetine still yielded a doxepin blood level (104 ng/mL) that was higher than what would have been obtained had doxepin been given as antidepressant monotherapy at the very low dosage of 25 mg/day (150–200 mg/day is more typical). personal communication. CYP2D6. May 2002). Agundez JA. A doxepin blood level performed on admission was only 104 ng/mL (D. the patient’s therapeutic response to doxepin. 1999. Removal of one of those inhibitors led to a decline in the doxepin blood level and a loss of antidepressant efficacy. 1999. May 2002.

the patient complained about dizziness. even though the warfarin dosage had not been changed. yielding an increase in R-warfarin. Fluoxetine (in concert with its active metabolite. the addition of the fluoxetine raised the INR through several mechanisms. 2000. Third. the internist discerned that the patient was struggling with the recent death of her husband and was frankly depressed. an increase in R-warfarin levels led to more inhibition of the metabolism of S-warfarin. 1996a. which led to an increase in the warfarin blood level. Ten days later. 1996b). Hesse et al. First. 25 mg/day. Thus. He chose to start the patient on fluoxetine (Prozac). 2C19. Oesterheld. R-warfarin does produce some direct anticoagulant effect. Sayal et al. 2000. Stevens and Wrighton 1993. Rwarfarin is itself an inhibitor of P450 2C9 (Kunze et al. Second. yielding higher S-warfarin levels. norfluoxetine) potently inhibits 2D6 and mildly to moderately inhibits 1A2. These combined influences caused a significant increase in the patient’s INR. Discussion This is an example of an inhibitor added to two substrates. 2C9. and 3A4 (Crewe et al. Second. metoprolol (Lopressor). Thus. fluoxetine significantly impaired the ability of 2C9 to efficiently metabolize S-warfarin.R. whose effects synergized to produce the complication described. July 2002). fluoxetine inhibited both 1A2 and 3A4. for neuropathic pain. This increase in the blood level of warfarin drastically increased the magnitude of warfarin’s anticoagulant effect. Once there. 20 mg/day.9). 2. No amitriptyline/nortriptyline levels were obtained (J. 1987. She contacted her internist. and 2D6. amitriptyline is a tertiary-amine tricyclic antidepressant whose metabolism depends most on the intact functioning of 2C19. As they spoke. a bladder catheterization yielded 2 liters of dark urine. and inability to void. dry mouth. 1992. Her INR was found to be 17. although it is a less potent anticoagulant than S-warfarin. The patient scheduled an appointment with her internist to discuss her persistent anergy and insomnia. 50 mg qhs. Linder and Valdes 1999). 1991). 2B6. warfarin’s metabolism is exceedingly complex. 1995. personal communication. . who advised her to call 911 and have an ambulance transport her to the nearest emergency room. but it mostly occurs at 2C9 for the more active S-warfarin isomer (Heimark et al. First.158 Drug–Drug Interaction Primer HEMATURIA A 72-year-old woman with type II diabetes mellitus and atrial fibrillation was being well maintained on warfarin (Coumadin). The less active R-warfarin isomer is metabolized primarily at 1A2 (Lehmann 2000). 5 mg/day (international normalized ratio [INR]. and amitriptyline (Elavil). Kobayashi et al.3. 3A4. von Moltke et al. Hemeryck and Belpaire 2002.

J Clin Pharmacol 38:112–121. leading to inability to void. Belpaire FM: Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug–drug interactions: an update. Gibaldi M. Clin Pharmacol Ther 42:388–394. a process along these lines is reasonably inferable. et al: Metabolic enantiomeric interactions: the inhibition of human (S)-warfarin-7-hydroxylase by (R)-warfarin. The fluoxetine significantly impaired the ability of 2D6. Greenblatt DJ. Chiba K. Lennard MS. et al: Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4. McConnell HW. et al: The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4′-hydroxylase activity in human liver microsomes. et al: CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Court MH. 2002 Hesse LM. 2000 Stevens JC. Gibaldi M. J Pharmacol Exp Ther 266:964–971. Drug Metab Dispos 28:1176–1183. Mol Diagn 4:365–379. 1991 Lehmann DE: Enzymatic shunting: resolving the acetaminophen-warfarin controversy. Taylor DM: Psychotropic interactions with warfarin. Trager WF. References Crewe HK. Tucker GT. 2000 Linder MW. Valdes R Jr: Pharmacogenetics in the practice of laboratory medicine. The combination of 1) fluoxetine’s elevation of the amitriptyline level (leading to anticholinergic-induced inability to void and subsequent bladder distension) and 2) fluoxetine’s elevation of the warfarin level (leading to a severely hypocoagulable state) caused spontaneous bleeding within the patient’s bladder. 2000 Kobayashi K. as evidenced by the increase in the anticholinergic effects of amitriptyline. 1992 Heimark LD. Br J Clin Pharmacol 40:481–485. 1998 . Chirality 3:24–29. et al: The effect of selective serotonin reuptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Even though this was unconfirmed by an actual blood level. and 2C19 to contribute to the metabolism of amitriptyline. which led to an increase in the blood level of amitriptyline + nortriptyline. 1999 Sayal KS. Duncan-McConnell DA. 1998). Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. 1993 Venkatakrishnan K. Venkatakrishnan K. Pharmacotherapy 20:1464–1468. von Moltke LL. Br J Clin Pharmacol 34:262–265. 3A4.Internal Medicine Case Vignettes 159 with 1A2 serving as a secondary enzyme (Venkatakrishnan et al. Curr Drug Metab 3:13–37. et al: The mechanism of the warfarin–rifampin drug interaction. Eddy AC. 1987 Hemeryck A. Acta Psychiatr Scand 102:250–255. This explains both the quantity and the color of the urine drained by catheterization of her bladder. Yamamoto T. 1995 Kunze KL.

2E1. 1996a von Moltke LL. and a long-standing seizure disorder that had been well controlled with carbamazepine. 1994) and a moderate 3A4 inhibitor (Eap et al. 2C9. 2004). 9. 2B6. A wound culture revealed infection with methicillin-resistant Staphylococcus aureus. with 1A2.2 µg/mL). during which she was transitioned to home care with intravenous antibiotic treatment. Duan SX. 3A4 and 2C9 were impaired in their ability to efficiently contribute to the metabolism of the carbamazepine. Psychopharmacology (Berl) 128:398–407. In the weeks after surgery. SSRI antidepressants. Three days later. after 1 week she experienced increasing drowsiness. 900 mg/day (blood level. her wound was not healing well. Because the activity of 1A2 was not sufficient to compensate for this effect. and she began to experience intermittent fevers. 2C8. She was treated with 8 weeks of intravenous vancomycin. 1996. Greenblatt DJ. the 3A4 and 2C9 inhibition resulted in an increased blood level of carbamazepine. 200 mg on day 1 and 100 mg/day thereafter for at least 2 weeks.160 Drug–Drug Interaction Primer von Moltke LL. confusion. With the addition of fluconazole. Carbamazepine is primarily a 3A4 substrate. The vancomycin successfully eradicated the infection. Staines et al. controlled by diet alone. However. Her medical comorbidities included type II diabetes mellitus. 2002). She was prescribed fluconazole (Diflucan). she was stuporous and required readmission to the hospital. and incoordination. even though the carbamazepine dosage had remained constant (Nair and Morris 1999). et al: Phenacetin O-deethylation by human liver microsomes in vitro: inhibition by chemical probes. In the emergency room. J Pharmacol Exp Ther 276:370–379. and phase II metabolism (uridine 5′-diphosphate glucuronosyltransferase [UGT] 2B7) making minor contributions to carbamazepine’s metabolism (Pearce et al. her carbamazepine level was 19.4 µg/mL. Harmatz JS. Spina et al. but the patient then developed a diffuse candidal rash. nefazodone and venlafaxine. Fluconazole is a strong 2C9 inhibitor (Cadle et al. . Greenblatt DJ. 2002. Discussion This is an example of an inhibitor added to a substrate. et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. 1996b COMPLICATIONS A 54-year-old woman was hospitalized with a severe right femur fracture that occurred during a skiing accident.

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References
Cadle RM, Zenon GJ 3rd, Rodriguez-Barradas MC, et al: Fluconazole-induced symptomatic phenytoin toxicity. Ann Pharmacother 28:191–195, 1994 Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet 41:1153–1193, 2002 Nair DR, Morris HH: Potential fluconazole-induced carbamazepine toxicity. Ann Pharmacother 33:790–792, 1999 Pearce RE, Vakkalagadda GR, Leeder JS: Pathways of carbamazepine bioactivation in vitro I. Characterization of human cytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites. Drug Metab Dispos 30:1170–1179, 2002 Spina E, Pisani F, Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Clin Pharmacokinet 31:198–214, 1996 Staines AG, Coughtrie MW, Burchell B: N-Glucuronidation of carbamazepine in Human Tissues is Mediated by UGT2B7. J Pharmacol Exp Ther 311:1131–1137, 2004

SECRET INGREDIENT
A 55-year-old man with a history of alcohol dependence, in full remission, had been taking disulfiram (Antabuse), 250 mg/day, for the past 5 years. One morning, he awakened with crushing substernal chest pressure radiating to the left arm and jaw, as well as significant shortness of breath. He called 911 and was quickly transported to the nearest emergency room. Once he arrived, the staff found he was having a myocardial infarction complicated by congestive heart failure. Among other interventions, he was placed on a continuous nitroglycerin intravenous infusion. Within 15 minutes of the initiation of this infusion, he developed nausea, increased chest pain and dyspnea, tachycardia, diaphoresis, flushing, and a throbbing headache. Once the patient revealed that he was taking disulfiram, the nitroglycerin infusion was immediately discontinued and he was rushed to the medical intensive care unit for more intensive monitoring and supportive care (K. Walters, personal communication, August 2002).

Discussion
This is an example of a substrate added to an inhibitor. Nitroglycerin solutions for intravenous infusion contain a significant amount of ethyl alcohol (“Nitroglycerin” 1999). Disulfiram’s main and intended function is to serve as a deterrent to the consumption of alcohol by virtue of its ability to inhibit aldehyde dehydrogenase, a key enzyme involved in the metabolism of ethyl alcohol. In the presence of alcohol, disulfiram’s in-

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hibition of this enzyme leads to an accumulation of acetaldehyde, resulting in the “disulfiram–alcohol reaction” (Kaplan and Sadock 1998) that this patient experienced. This interaction, even in generally healthy persons, has produced severe morbidity and even death, which has led to a decline in the popularity of disulfiram as a means of fostering abstinence from alcohol. When the emergency room physician recognized that this patient was having just such a reaction, he quickly discontinued the supply of the substrate (alcohol in the nitroglycerin infusion) and intensified the level of monitoring and care available to the patient.

References
Kaplan H, Sadock B: Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 8th Edition. Baltimore, MD, Williams and Wilkins, 1998 Nitroglycerin, in MICROMEDEX Healthcare Series. Greenwood Village, CO, Micromedex Inc, 1974–1999

FIBRILLATIONS
A 65-year-old widower with atrial fibrillation was taking digoxin (Lanoxin), 0.25 mg/day (blood level, 0.8 ng/mL), for rate control and one aspirin each day as an anticlotting agent. This regimen had been generally effective, producing average resting heart rates in the range of 60–80 beats per minute. After his pet bull terrier died, the man became more dysphoric and demoralized. He did not want to discuss his feelings with any of his doctors, so he instead opted to visit the local drugstore and purchase St. John’s wort (Hypericum perforatum), which he then began to consume per the pharmacist’s instructions. In about 2 weeks, he noticed the sensation that his heart was racing, and his pulse felt to him like it was faster than 100 beats per minute. He called his doctor, who instructed him to call 911 immediately. The heart monitor in the ambulance confirmed that he was again in rapid atrial fibrillation, and his digoxin blood level in the emergency room had declined to 0.5 ng/mL.

Discussion
This is an example of an inducer added to a substrate. Digoxin is a substrate of the P-glycoprotein transport protein (PauliMagnus et al. 2001), and St. John’s wort is an inducer of P-glycoprotein (Hennessy et al. 2002). Thus, the addition of the St. John’s wort led to the increased production of this transporter, which was therefore more active in extruding digoxin from enterocytes and back into the gut lumen, where it

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was excreted rather than absorbed. This caused a corresponding decline in the digoxin blood level, rendering the digoxin less effective in providing rate control of the patient’s atrial fibrillation. Studies have demonstrated a 33% decrease in digoxin blood levels when St. John’s wort is added for at least 10 days (Johne et al. 1999).

References
Hennessy M, Kelleher D, Spiers JP, et al: St. John’s wort increases expression of Pglycoprotein: implications for drug interactions. Br J Clin Pharmacol 53:75–82, 2002 Johne A, Brockmoller J, Bauer S, et al: Pharmacokinetic interaction of digoxin with an herbal extract from St. John’s wort (Hypericum perforatum). Clin Pharmacol Ther 66:338–345, 1999 Pauli-Magnus C, Murdter T, Godel A, et al: P-glycoprotein–mediated transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin. Naunyn Schmiedebergs Arch Pharmacol 363:337–343, 2001

ST. SEROTONIN
A 28-year-old woman with dysthymic disorder had been prescribed paroxetine (Paxil), 20 mg/day, by her primary care physician. She had not yet enjoyed a positive response to this medication, so she unilaterally decided to augment the paroxetine with St. John’s wort (Hypericum perforatum). Within 5 days, she experienced increasing nausea, agitation, ataxia, diaphoresis, muscle stiffness, and tremor. She reported these symptoms to her physician, who then advised her to call 911 and report to the nearest emergency room. Once there, she was admitted to the medical floor and treated with muscle relaxants, lorazepam (Ativan), and antipyretics for the fevers that she had begun to experience on admission. She was discharged in good condition 3 days later. The primary care physician obtained preauthorization from the patient’s health maintenance organization for her to obtain subsequent psychiatric care from a psychiatrist.

Discussion
This is an example of a central serotonin syndrome, moderate in severity, arising from two complementary mechanisms. First, both paroxetine (a selective serotonin reuptake inhibitor) and St. John’s wort have significant abilities to inhibit serotonin reuptake. When these agents are combined, these effects are additive, which contributed significantly to the development of the serotonin syndrome. Second, St. John’s wort also acts as a weak monoamine oxidase inhibitor (Gnerre et al.

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2001). Because serotonin is a monoamine, the St. John’s wort therefore inhibited the metabolic breakdown of serotonin by monoamine oxidase. This further increased the level of serotonin activity, and this increase synergized with the additive serotonin reuptake inhibition of the two agents to produce a central serotonin syndrome (DeVane and Nemeroff 2002; Izzo 2004).

References
DeVane CL, Nemeroff CB: 2002 guide to psychotropic drug interactions. Prim Psychiatry 9:28–57, 2002 Gnerre C, von Poser GL, Ferraz A, et al: Monoamine oxidase inhibitory activity of some Hypericum species native to south Brazil. J Pharm Pharmacol 53:1273– 1279, 2001 Izzo AA: Drug interactions with St. John’s Wort (Hypericum perforatum): a review of the clinical evidence. Int J Clin Pharmacol Ther 42:139–148, 2004

THE CURSE OF ZOSTER
A 45-year-old man began to experience severe and debilitating postherpetic neuralgia pain (right-sided ophthalmic and maxillary distribution) about 3 years ago. After several unsuccessful attempts at treatment, the neurologist eventually prescribed morphine as MS Contin, 100 mg bid, which controlled the patient’s extreme pain. Two months ago, the patient reported persistent cough, malaise, and fevers to his internist, and he was eventually diagnosed with tuberculosis. Among other medications, he was placed on rifampin (in the form of Rifadin). One week after the rifampin was started, he began to experience the reemergence of his neuralgia pain, and MS Contin, 100 mg bid, was again prescribed to address this. One week later, the pain was almost as bad as it had been before the MS Contin was started. The neurologist immediately began to titrate the MS Contin dose upward. The patient reachieved his baseline of easily tolerated pain only after an MS Contin dosage of 180 mg bid had been reached.

Discussion
This is an example of an inducer added to a substrate. Morphine is a substrate of the P-glycoprotein transport protein (Wandel et al. 2002), and rifampin is an inducer of P-glycoprotein (Geick et al. 2001). Thus, the addition of rifampin led to an increased production of this transporter, which was therefore more active in extruding morphine from enterocytes and back into the gut lumen, where it was excreted rather than absorbed. This caused a corresponding decline in the blood level of morphine, rendering the original dosage much less effective in controlling the

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patient’s postherpetic neuralgia pain. One study demonstrated a 28% decrease in the morphine area under the curve, a 41% decrease in the maximum blood level of morphine, and a loss of analgesic efficacy after rifampin was added for a 2-week period (Fromm et al. 1997).

References
Fromm MF, Eckhardt K, Li S, et al: Loss of analgesic effect of morphine due to coadministration of rifampin. Pain 72:261–267, 1997 Geick A, Eichelbaum M, Burk O: Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276:14581–14587, 2001 Wandel C, Kim R, Wood M, et al: Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology 96:913–920, 2002

NAUSEATED NANNY
A 40-year-old nanny with recurrent major depression had done well for the past 9 months on the regimen of citalopram (Celexa), 20 mg/day; venlafaxine (Effexor), 300 mg/day (added 10 months ago); and lithium, 1,050 mg/day (blood level, 0.85 mEq/L). During a routine appointment with her internist, she was found to have a blood pressure of 170/100 mm Hg. After discussing various options with the patient, the internist prescribed lisinopril (Zestril), which was quickly titrated to a dosage of 30 mg/day. Within 1 week of reaching this dosage, however, the patient contacted both her psychiatrist and her internist to report a coarse intention tremor, blurry vision, and persistent nausea with vomiting once each day. The psychiatrist suggested that she report to the nearest emergency room for a lithium level, which was found to be 1.4 mEq/L (Baldwin and Safferman 1990).

Discussion
This is an example of mild lithium toxicity caused by a drug that inhibits the production of aldosterone. Lithium is excreted primarily by the kidney. Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor. (ACE is the enzyme that converts angiotensin I into angiotensin II.) Angiotensin II, in addition to being a vasoconstrictor, promotes the release of the hormone aldosterone, which acts at the kidney to retain sodium and excrete potassium. Because ACE inhibitors ultimately inhibit the release of aldosterone, they shift the renal handling of sodium in the direction of decreased retention and increased excretion. Sodium and lithium compete for reabsorption at the proximal tubule of the nephron. With relatively less sodium being retained because

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of ACE inhibitor–induced decreases in aldosterone release, lithium is better able to compete for reabsorption, leading to increased lithium retention and possible toxicity (Finley et al. 1996).

References
Baldwin CM, Safferman AZ: A case of lisinopril-induced lithium toxicity. DICP 24:946–947, 1990 Finley PR, O’Brien JG, Coleman RW: Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction. J Clin Psychopharmacol 16:68–71, 1996

RESISTANCE
A 45-year-old man with panic disorder had been free of panic attacks for 3 years while taking paroxetine (Paxil), 40 mg/day. One summer, he was hospitalized after his right arm and hand were badly mutilated by a lawnmower he was attempting to repair. In the week after surgery, he began to experience intermittent fevers and felt especially weak. Blood cultures were positive for methicillin-resistant Staphylococcus aureus. The patient was placed on a therapeutic dosage of vancomycin, and his fevers abated in a few days. However, 1 week after the vancomycin was started, his fevers and a renewed feeling of malaise and nausea returned. Another set of blood cultures now revealed a vancomycin-resistant Enterococcus faecium bacteremia. The vancomycin was discontinued, and he was placed on linezolid (Zyvox), 600 mg iv every 12 hours. The patient was still taking his paroxetine at the regular dosage. Within 2 days, the patient was acutely delirious, febrile to 104°F, hypertensive, vomiting, and experiencing myoclonus. The patient was immediately taken to the intensive care unit for more intensive care and monitoring (Wigen and Goetz 2002).

Discussion
This is an example of an inhibitor added to a substrate. Paroxetine is a potent selective serotonin reuptake inhibitor (SSRI). SSRIs increase serotonergic neurotransmission and overall availability of serotonin. Linezolid, in addition to being an antibiotic, is a reversible but nonselective monoamine oxidase inhibitor, and as such it inhibits the breakdown of serotonin. The combination of these two mechanisms of action resulted in a toxic accumulation of serotonin, manifesting as an acute serotonin syndrome (Wigen and Goetz 2002) with autonomic instability and delirium. This interaction has been demonstrated with linezolid and other SSRIs as well (Bernard et al. 2003; Clark et al. 2006)

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References
Bernard L, Stern R, Lew D, et al: Serotonin syndrome after concomitant treatment with linezolid and citalopram. Clin Infect Dis 36:1197, 2003 Clark DB, Andrus MR, Byrd DC: Drug interactions between linezolid and selective serotonin reuptake inhibitors: case report involving sertraline and review of the literature. Pharmacotherapy 26:269–276, 2006 Wigen CL, Goetz MB: Serotonin syndrome and linezolid. Clin Infect Dis 34:1651– 1652, 2002

THE TREMULOUS TRUCKER
A 49-year-old truck driver with bipolar I disorder had maintained good clinical stability while taking risperidone (Risperdal), 2 mg qhs, and lithium, 900 mg/day (mean blood level, 0.9 mEq/L) for the past 3 years. During an appointment with his internist, the patient’s blood pressure was found to be 175/100 mm Hg. His internist prescribed valsartan (Diovan), 80 mg/day, and asked him to return in 3 months for a follow-up appointment. Three days later, the patient noticed that his hands were oddly tremulous, requiring him to grip the steering wheel firmly with both hands to ensure that he retained control of his vehicle. The tremors grew worse over the ensuing 4 days, as did his fatigue and mild confusion. When he woke up the next morning, he had trouble maintaining his balance while trying to walk. He then reported his difficulties to his internist, who advised him to report to the nearest emergency room, where his lithium level was found to be 1.4 mEq/L (“Lithium/Valsartan Possible Interaction” 2000).

Discussion
This is an example of mild lithium toxicity caused by valsartan, a medication that inhibits the production of aldosterone. Lithium is excreted by the kidney. Valsartan is an angiotensin II receptor antagonist. Under normal circumstances, circulating angiotensin II binds to specific receptors, which then trigger aldosterone release. Angiotensin II receptor antagonists, such as valsartan, inhibit the ability of angiotensin II to stimulate aldosterone release. Because aldosterone is a hormone that promotes the retention of sodium and the excretion of potassium, the inhibition of aldosterone release leads to increased sodium excretion and potassium retention. Sodium and lithium compete for reabsorption at the proximal tubule of the nephron. With relatively less sodium being retained because of angiotensin II receptor antagonist–induced decreases in aldosterone release, lithium is better able to compete for reabsorption, leading to increased lithium retention and possible toxicity (Blanche et al. 1997). In this case, the lithium level increased by roughly 50%.

168

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References
Blanche P, Raynaud E, Kerob D, et al: Lithium intoxication in an elderly patient after combined treatment with losartan. Eur J Clin Pharmacol 52:501, 1997 Lithium/valsartan possible interaction. Psychiatry Drug Alerts 14:55, 2000

STUPOR
A 57-year-old man had been receiving 800 mg/day of carbamazepine (Tegretol) (blood level, 10.7 µg/mL) for the successful treatment of trigeminal neuralgia. He had also been experiencing increasing heartburn and obvious gastroesophageal reflux. He reported these symptoms to his internist, who prescribed omeprazole (Prilosec), 20 mg/day, for the patient. One week later, the patient noted increasing fatigue, dizziness, and diplopia. His wife informed him that his eyes were fluttering at times. Over the next 4 days, the patient became increasingly confused and even frankly stuporous at times. The patient’s wife finally brought him to the local emergency room, where his carbamazepine level was found to be 19.5 µg/mL (Dixit et al. 2001).

Discussion
This is an example of an inhibitor added to a substrate. An examination of possible P450-related factors that could affect this interaction is a confusing enterprise. First, carbamazepine is primarily a 3A4 substrate, with 1A2, 2B6, 2C8/9, 2E1, and phase II metabolism (uridine 5′-diphosphate glucuronosyltransferase [UGT] 2B7) making minor contributions to carbamazepine’s metabolism (Pearce et al. 2002; Spina et al. 1996; Staines et al. 2004). Omeprazole is an inhibitor of 2C19 and an inducer of 1A2 (Furuta et al. 2001; Nousbaum et al. 1994). The sum of these factors suggests that the addition of omeprazole should lead to a modest decrease in the blood level of carbamazepine via induction of 1A2. There are no known relevant glucuronidation issues here. However, carbamazepine is a substrate of the P-glycoprotein transporter (Potschka et al. 2001), and omeprazole is an inhibitor of the activity of this transporter (Pauli-Magnus et al. 2001). Thus, the addition of omeprazole significantly impaired the ability of the P-glycoprotein transporter to extrude carbamazepine from enterocytes back into the gut lumen. Because more carbamazepine was retained in enterocytes, there was greater bioavailability and absorption of carbamazepine from the gut, leading to an increase in the blood level of carbamazepine (Dixit et al. 2001). Carbamazepine blood level increases of 50%–100% with this combination are not unusual.

Am J Gastroenterol 89:371–375. et al: Four-week treatment with omeprazole increases the metabolism of caffeine. Burchell B: N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. Naunyn Schmiedebergs Arch Pharmacol 364:551–557. . 1994 Pauli-Magnus C.Internal Medicine Case Vignettes 169 References Dixit RK.and 3-hydroxylated metabolites. et al: Effect of omeprazole on the pharmacokinetics of sustained-release carbamazepine in healthy male volunteers. and there was some concern that this represented a transient ischemic attack. 85 µg/mL). Rekersbrink S. 325 mg/day. When this persisted for more than 30 minutes. he reported sudden onset of terrific fatigue and sedation. Leeder JS: Pathways of carbamazepine bioactivation in vitro I. 1996 Staines AG. who advised the patient to report to the local emergency room for an evaluation. et al: Inhibition of drug metabolism in human liver microsomes by nizatidine. Kamada E. given the patient’s as yet untreated hypertension (155/95 mm Hg) and family history that was positive for stroke. the internist again recommended that the patient visit the emergency room. 2004 DISPLACED A 48-year-old man with a history of bipolar I disorder was responding well to treatment with divalproex sodium (Depakote). and aspirin. Klotz U. Chawla AB. 2001 Furuta S. Kumar N. One morning. He was given enalapril (Vasotec). J Pharmacol Exp Ther 311:1131–1137. Carlhant D. 2002 Potschka H. Drug Metab Dispos 30:1170– 1179. Loscher W: P-glycoprotein and multidrug resistanceassociated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. Vakkalagadda GR. Fearing a cerebrovascular accident. 2001 Spina E. as well as incoordination. 2001 Nousbaum JB. Within 3 days.250 mg/day (blood level. 2001 Pearce RE. Neuroreport 12:3557–3560. Clin Pharmacokinet 31:198–214. Fedrowitz M. Suzuki T. et al: Interaction of omeprazole. 500 mg/day. Characterization of human cytochromes P450 responsible for the formation of 2. he awoke to the sensation of mild tingling in his right hand and lower arm. Berthou F. This symptom spontaneously abated after 4 hours. Coughtrie MW. and quetiapine (Seroquel). 5 mg bid. Xenobiotica 31:1–10. A consulting neurologist commented that his presentation was consistent with valproate toxicity. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Methods Find Exp Clin Pharmacol 23:37–39. 1. cimetidine and omeprazole. lansoprazole and pantoprazole with P-glycoprotein. the patient contacted his internist. Pisani F. yet the divalproex blood level was essentially unchanged at 95 µg/mL.

The existing literature reports that combinations of valproate with “antipyretic” doses of aspirin (approximately 3. These two factors combine to produce modest increases in total valproate levels. and the addition of aspirin to divalproex leads to mutual displacement from plasma protein binding sites and a corresponding rise in the free fraction of each drug. Neurology 37:1392–1394. In this case. References Abbott FS. Grimaldi et al. 1986. et al: The effect of acetylsalicylic acid on serum free valproate concentrations and valproate clearance in children. Farrell et al. However. J Pediatr 101:142– 144. Kassam J. 1984. 1986 Abbott Laboratories: Depakote (package insert). Additionally. 2006).170 Drug–Drug Interaction Primer Discussion This is an example of plasma protein binding displacement accompanied by metabolic inhibition. 1987 . 1986). 1982 Goulden KJ. 2006) suggest that the necessary dosage of aspirin to increase free valproate levels might be considerably lower than that. Clin Pharmacol Ther 40:94–100. such as phenytoin and nonsteroidal anti-inflammatory drugs (Abbott Laboratories 2002. et al: The effect of aspirin on valproic acid metabolism. there has never been a rigorous attempt to establish the lowest dosage of aspirin that can produce this effect. Aspirin is also highly plasma protein– bound (Lim et al. This case and others like it (Sandson et al. Kodama et al. Goulden et al. IL. it is especially important to follow free concentrations with this combination as well as other interactions in which there is a combination of protein binding displacement and metabolic inhibition (such as adding valproate or non-aspirin nonsteroidal anti-inflammatory drugs to phenytoin) (Sandson et al. Abbott Laboratories. aspirin is an inhibitor of β-oxidation. North Chicago. 2001). Divalproex is tightly bound to plasma proteins and thus may displace and be displaced by other tightly bound compounds. Because this interaction can produce greater increases in free concentrations than in total concentrations of valproate. 2002 Farrell K. Orr JM. Orr JM. et al: Clinical valproate toxicity induced by acetylsalicylic acid.900 mg/day) can produce up to fourfold increases in free valproate (Orr et al. 1982. and this process is responsible for roughly 40% of valproate’s metabolism. the marked increase in the free/active concentration led to the development of marked sedation and incoordination. but disproportionate and often clinically significant increases in free valproate concentrations (Abbott et al. Abbott FS. 1982). Dooley JM. Camfield PR. 1987). This occurs because it is the metabolism of the free fraction that is being inhibited.

as an anticoagulant after her mitral valve replacement procedure. Lecchini S. Hamilton W. 1986 Orr JM. et al: An interaction between aspirin and valproate: the relevance of plasma protein displacement drug–drug interactions. She quickly reported to a local emergency room. Crema F. 2000 Yu CM.8 and her partial thromboplastin time was greater than 120 seconds (Yu et al. Wynne KN. Am J Psychiatry 163:1891–1896. 2001 Lim CF. Eur J Pharm Biopharm 52:57–63. These anticoagulant effects synergized to produce spontaneous hemorrhagic events. 2006 HERBAL HEMORRHAGE A 35-year-old woman with rheumatic heart disease had been taking warfarin (Coumadin). who recommended danshen (Salvia miltiorrhiza) for this problem.2). Abbott FS. Danshen is able to inhibit platelet aggregation (Lambrecht et al. but fortunately not to a fatal extent in this case.S. Farrell K. U. et al: In vivo plasma protein binding interaction between valproic acid and naproxen. She was experiencing menstrual irregularity. et al: Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects. Within the next week. 1997 . 1984 Kodama Y. 5 mg/day (international normalized ratio [INR]. Warfarin functions as an effective anticoagulant by virtue of its ability to inhibit specific steps of the coagulation cascade. 1982 Sandson N. Discussion This is an example of pharmacodynamic synergy resulting in excessive anticoagulation. as measured by the INR. Barned JM.Internal Medicine Case Vignettes 171 Grimaldi R.or age-related binding characteristics of valproic acid to serum proteins in adult patients with epilepsy. Bourke DL. Chan JC. 1997). 2000). J Pharm Pharmacol 38:795– 800. where her INR was 9.’ J Intern Med 241:337–339. Sanderson JE: Chinese herbs and warfarin potentiation by ‘danshen. Pharmacist Home 25:8. Rabinovich A: A review of herb–drug interactions: documented and theoretical. et al: Gender. et al: Non-isotopic spectrophotometric determination of the unbound fraction of drugs in serum. Marcucci C. the woman was alarmed to discover she was experiencing spontaneous subcutaneous hematoma formation. Clin Pharmacol Ther 31:642–649. so she visited an herbalist. References Lambrecht JE. Eur J Drug Metab Pharmacokinet 9:359– 363. 3. Kodama H. Kuranari M.

S. 2000 FATAL ERROR A 53-year-old woman with type II diabetes mellitus and atypical major depression was being stably maintained by taking tranylcypromine (Parnate). Ginseng appears to possess some procoagulant effects that decrease the INR. References Janetzky K. Before she could seek help. so her new internal medicine resident at her clinic started her on imipramine (Tofranil). who called 911. she was experiencing a severe headache. Am J Health Syst Pharm 54:692–693. He was found to be having a transient ischemic attack. Morreale AP: Probable interaction between warfarin and ginseng. The addition of ginseng to the warfarin antagonized some of warfarin’s anticoagulant efficacy. and his INR was only 1. He decided to purchase some ginseng and took it as directed by the herbalist. 50 mg/day for 3 days and 100 mg/day thereafter. and myoclonus. U. Rabinovich A: A review of herb–drug interactions: documented and theoretical. He promptly called an ambulance and was transported to the nearest emergency room. 1997 Lambrecht JE.5 mg/day (international normalized ratio [INR]. she was found to have a blood . tremors. 5 mg/day. Hamilton W. Discussion This is an example of conflicting pharmacodynamic effects. Pharmacist Home 25:8. 2000).172 Drug–Drug Interaction Primer TRANSIENT ISCHEMIC ATTACK A 65-year-old man with a history of atrial fibrillation with regular rate and prior cerebral vascular accidents was being maintained on warfarin (Coumadin). She was eventually discovered by her daughter. and glipizide (Glucotrol). She began to experience some neuropathic pain in her feet. vomiting. she experienced a seizure and was incapacitated.6). Warfarin functions as an effective anticoagulant by virtue of its ability to inhibit specific steps of the coagulation cascade. he awoke with a tingling sensation over the lower left side of his face. which might lead to transient ischemic attacks or cerebrovascular accidents. 2. Once in the emergency room. 60 mg/day. although the precise nature of these is not yet well understood (Lambrecht et al. Within 1 week. Three weeks later. A friend told him about ginseng (Panax ginseng) as a means of improving cognitive function and one’s overall sense of well-being. 2. making this patient vulnerable to clot formation.4 (Janetzky and Morreale 1997). as measured by the INR.

The cause of death was determined to be attributable to myocardial infarction. and these monoamines were more available and active throughout the body.Internal Medicine Case Vignettes 173 pressure of 290/150 mm Hg.S. and dopamine) was inhibited. References GlaxoSmithKline: Parnate (package insert). Little. which caused a severe hemorrhagic cerebrovascular accident. the results were fatal. Serbian dictator Slobodan Milosevic had been receiving unspecified medications for his hypertension and coronary artery disease. In early March 2006. 8th Edition. Baltimore. MA. Williams and Wilkins. norepinephrine. Tranylcypromine is a monoamine oxidase inhibitor (MAOI). epinephrine. Because he did not carry the diagnosis of tuberculosis. it is even more dangerous when the TCA is added to a full dose of an MAOI. as opposed to the reverse sequence (Hyman et al. he was found dead. Discussion This is an example of a “substrate” added to an inhibitor. which resulted in a hypertensive crisis superimposed on a severe central serotonin syndrome (GlaxoSmithKline 2001). 1998 DEAD MEN TELL NO TALES During his war crimes trial at The Hague. a Dutch toxicologist found traces of rifampicin (rifampin in the U. 2001 Hyman S. Arana G. Imipramine is a tricyclic antidepressant (TCA) with a mixed serotonergic and noradrenergic reuptake inhibition profile. . Brown. 1995 Kaplan H. days before he was scheduled to conclude his testimony. NC. 3rd Edition. Efforts to resuscitate her were unsuccessful. and she expired. and she was in the throes of a severe central serotonin syndrome.) in his blood. Boston. MD. Soon thereafter. Rosenbaum J: Handbook of Psychiatric Drug Therapy. which also caused these two neurotransmitters to be more available and active (Kaplan and Sadock 1998). Sadock B: Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. Research Triangle Park. 1995). this finding led to suspicions of foul play. In this case. Whereas this is a perilous combination of medications under the best of circumstances. GlaxoSmithKline. The combination of these reuptake inhibition and monoamine oxidase inhibition influences led to a state of catecholamine and serotonin excess. so the breakdown of monoamines (serotonin.

et al: The mechanism of the warfarin– rifampin drug interaction. or design. whether by accident. Arch Intern Med 157:2453–2458. Eur J Clin Pharmacol 56:299–304. 1997. Kay et al. . Milosevic was taking. calcium channel blockers. Thong NQ. Zilly et al. it is reasonable to assume that their metabolism was induced by the rifampin. 1998 Zhou HH. Br J Clin Pharmacol 20:323–326. 1997 Wietholtz H. This is known to be the case for various β-blockers. Br J Clin Pharmacol 30:471–475. Richter E: Stimulation of drug metabolism by rifampicin in patients with cirrhosis or cholestasis measured by increased hexobarbital and tolbutamide clearance. 2000. 1987. 1977 TREATMENT FAILURE A 72-year-old female with a lifelong seizure disorder had been well maintained on phenytoin (Dilantin). Rifampin is a pan-inducer of assorted P450 and phase II enzymes (Ebert et al. 1985. 1998). Oertel R. et al: Influence of rifampicin and isoniazid on the kinetics of phenytoin. Amar J: Drug interactions with antihypertensive drugs. Trager WF. 1995 Ebert U. Breimer DD. et al: Effects of rifampin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. 1990. Zhou et al. References Chamontin B. Anthony LB. Patterson JH. Zysset T. this episode briefly made the world aware of the potential for drug interactions to have deadly consequences. 1977). Strayhorn et al. et al: The influence of rifampin treatment on caffeine clearance in healthy man. Gibaldi M. Heimark et al. et al: Induction of polymorphic 4′ hydroxylation of S-mephenytoin by rifampicin. 1987 Kay L. angiotensin-converting enzyme inhibitors. 2000 Heimark LD. 1985 Strayhorn VA. McQueen RH. 1990 Zilly W. and angiotensin receptor blockers (Chamontin and Amar 1995. Clin Pharmacol Ther 42:388–394. Svendsen TL. 17.174 Drug–Drug Interaction Primer Discussion This is an example of an inducer added to a substrate. 1995. III. Therapie 50:221–226.6 µg/mL). Kampmann JP. Wood AJ. 1995 Williamson KM. Theories differ as to whether the presence of rifampin in his blood represented a pharmacologic assassination or a self-inflicted attempt to merit a medical release from The Hague gone awry. misadventure. In either case. 400 mg/day (blood level. Eur J Clin Pharmacol 11:287–293. Williamson et al. Baciewicz AM. Wietholtz et al. et al: Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers. J Hepatol 22:78–81. Self TH: Update on rifampin drug interactions. Marschall HU. Although it is not known exactly what antihypertensive medications Mr. Clin Pharmacol Ther 63:316–323.

Ann Intern Med 102:559. This led to an increase in the blood level of phenytoin (Gillman and Sandyk 1985. In this patient. She reported these symptoms to her internist.3 µg/mL. 1979 Mamiya K. who opted to treat her with a 3-day course of trimethoprim-sulfamethoxazole (Bactrim). 1979) . et al: The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. Shimamoto J. Sulfamethoxazole is a known inhibitor of P450 2C9 (Wen et al. Acta Med Scand Suppl 624:106– 110. Kampmann JP. A phenytoin level drawn at this time had risen to 26. Mamiya et al. Even though the Bactrim cleared her urinary tract infection. Sandyk R: Phenytoin toxicity and co-trimoxazole. 2002 THE CLOT THICKENS A 45-year-old female with AIDS had been chronically treated with trimethoprim-sulfamethoxazole (TMP/SMX. During this course of treatment. the addition of sulfamethoxazole impaired the ability of 2C9 to significantly contribute to the metabolism of phenytoin. somnolent. this produced a moderately delirious state that included urinary incontinence. Siersbaek-Nielsen K. Epilepsia 39:1317–1323. She began to experience increasing urinary frequency and dysuria. Wang JS. Backman JT. Following placement on chronic TMP/ . Hansen et al. 1985 Hansen JM. Ann Pharmacother 28:191–195. 1998 Wen X. Rodriguez-Barradas MC. Drug Metab Dispos 30:631–635. 1994 Gillman MA. and frankly incontinent of urine. 1994. or Bactrim) for Pneumocystis carinii pneumonia (PCP) prophylaxis. and her urine eventually became notably malodorous. the overall treatment was complicated by the unanticipated drug interaction. 1998). References Cadle RM. et al: Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9. respectively. 2002). et al: The effect of different sulfonamides on phenytoin metabolism in man. Discussion This is an example of an inhibitor added to a substrate. et al: Fluconazole-induced symptomatic phenytoin toxicity. the plumbing in her house failed and she had some difficulty remaining well hydrated.Internal Medicine Case Vignettes 175 During an especially hot summer. Zenon GJ 3rd. Ieiri I. the patient became somewhat confused. Thus.

4 mg/day (international normalized ratio [INR]. the patient experienced acute onset of slurred speech and right sided hemiparesis. J Gen Intern Med 20:653–656. Prochazka AV: The risk of overcoagulation with antibiotic use in outpatients on stable warfarin regimens. However. 2005. The more active S-warfarin isomer is metabolized primarily by P450 2C9 (Heimark et al. Linder and Valdes 1999). the patient’s internist opted to discontinue the TMP/SMX in accordance with recent research regarding appropriate PCP prophylaxis. 2. With the discontinuation of the TMP/SMX. 2C9 was impaired in its ability to contribute to the metabolism of warfarin. At this time.4). which predisposed her to a cerebrovascular accident in the context of undertreated atrial fibrillation. Warfarin’s metabolism is very complex. With appropriate highly active antiretroviral therapy. the patient’s CD4 count rose to a value of 257/mm3. 2005 . if the drug interaction is not recognized. where a computed tomography scan of the brain confirmed an acute ischemic stroke. then one is unlikely to anticipate the decreases in substrate levels that can occur with the discontinuation of enzymatic inhibitors (or the increases in substrate levels that can occur with the discontinuation of enzymatic inducers). provided that one is dosing substrate in accordance with blood levels. 1987. 2002). Kaufman and Fauver 1980). This led to higher blood levels of warfarin and a higher INR than would have occurred at the same dosage without the TMP/SMX (Glasheen et al. Sulfamethoxazole is a known inhibitor of P450 2C9 (Wen et al. References Glasheen JJ. The patient was taken to the nearest emergency room. Fugit RV.5. and/or side effects rather than per preset dosing guidelines. Discussion This is an example of a substrate added to an inhibitor.176 Drug–Drug Interaction Primer SMX. clinical response. Thus. 2C9 was able to resume its higher baseline level of activity. followed by reversal of inhibition. However. when warfarin was added to TMP/SMX. 2 weeks after the TMP/SMX had been discontinued. she then developed atrial fibrillation and was additionally treated with warfarin (Coumadin). This produced a decrease in warfarin levels and a corresponding drop in the patient’s INR. This case also illustrates the importance of recognizing drug interactions even when they do not produce acute difficulties. Her INR in the emergency room had declined to 1. Additions of substrates to inhibitors (or inducers) often do not produce acute complications.

However. Within 3 hours of her first dose. the patient had begun taking an oral contraceptive containing ethinylestradiol. which was effective and well-tolerated. Incidentally. Her only current medication was an oral contraceptive. the emergency room physician prescribed naproxen (Naprosyn). et al: Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9. Drug Metab Dispos 30:631–635. Wang JS. 1999 Wen X. which is an inhibitor of 2C19 (Shelepova et al. This additional compromise of this enzyme led to further increases in carisoprodol blood levels at standard dosages. Trager WF. 1987 Kaufman JM. 2002 SOMATIC SEDATION A 38-year-old female reported to a local emergency room due to sudden onset of back pain after helping a friend to move from her apartment. While in the emergency room. . 2005). when she had previously taken carisoprodol many years ago. which was helpful for her back pain and did not produce any further difficulties. Mol Diagn 4:365–379. Urology 16:601–603.Internal Medicine Case Vignettes 177 Heimark LD. she reported that when she hurt her back in a similar manner about 10 years previously. et al: The mechanism of the warfarin–rifampin drug interaction. Discussion This is an example of a substrate added to an inhibitor. The emergency room physician gave her a prescription for carisoprodol. personal communication. The fact that the patient was an intermediate metabolizer at 2C19 means that her carisoprodol blood levels were higher at a given dosage than they would have been if she had the normal form of this enzyme (extensive metabolizer phenotype). she experienced marked somnolence and confusion. Since that time. 1980 Linder MW. 500 mg bid. which she started taking 3 years ago. previous genotyping revealed that the patient was an intermediate metabolizer for P450 2C19 (J. her physician prescribed carisoprodol (Soma). Backman JT. Carisoprodol is a substrate of P450 2C19 (Dalen et al. Her friend brought her back to the emergency room. Valdes R Jr: Pharmacogenetics in the practice of laboratory medicine. respectively. Fauver HE: Potentiation of warfarin by trimethoprim-sulfamethoxazole. to the point that the patient experienced an acute episode of delirium. Gibaldi M. Oesterheld. 1996). where she spent the next several hours sleeping. her complement of 2C19 provided sufficiently efficient metabolism of the drug for her to tolerate it without difficulty. January 2006). When she awoke. Clin Pharmacol Ther 42:388–394.

Because glipizide is an oral hypoglycemic agent. with accompanying clinical signs of hypoglycemia. there was a more-than-sixfold greater likelihood of exposure to TMP/SMX in the week prior to admission. whereupon she was admitted to the nearest hospital to stabilize her glycemic status and address her diabetes management (Johnson and Dobmeier 1990). 2005]) and hospitalized due to hypoglycemia. she shared her complaints of frequency and dysuria for the past month. Discussion This is an example of an inhibitor added to a substrate. even though the glipizide dosage had not been increased. A study by Juurlink et al. the patient had become anxious. Glipizide is a 2C9 substrate (Kidd et al. The addition of the TMP/ SMX led to a significant impairment in the ability of 2C9 to efficiently metabolize the glipizide.178 Drug–Drug Interaction Primer References Dalen P. and somewhat confused. A blood glucose was found to be 41 mg/dL. and she was found to have a urinary tract infection with a strain of Escherichia coli that was susceptible to trimethoprim-sulfamethoxazole (TMP/SMX or Bactrim). dizzy. Nafziger AN. 2005 PROBABILITIES A 79-year-old female nursing home resident enjoyed good glycemic control of her type II diabetes mellitus with glipizide (Glucotrol). Her internist started her on a 3-day course of TMP/SMX. During a routine check-in by her internist. 2002). Pharmacogenetics 6:387–394. diaphoretic. J Clin Pharmacol 45:1413–1421. (2003) demonstrated that in patients older than age 66 who were treated with glyburide (also a 2C9 substrate [Kirchheiner et al. . et al: Effect of triphasic oral contraceptive on drug-metabolizing enzyme activity as measured by the validated Cooperstown 5+ 1 cocktail. so a decrease in the glipizide dosage for 1–2 days followed by a restoration of glipizide to its original (higher) dosage would be a prudent treatment plan at this juncture. Wakelkamp M. 5 mg bid. This effect remits following the completion of treatment with TMP/SMX. 2001). By the third day. an increase in the glipizide blood level led to a decrease in the patient’s blood glucose. Consequently. 1996 Shelepova T. Her urine was cultured. Victory J. Alvan G. whereas sulfamethoxazole is an inhibitor of 2C9 (Wen et al. et al: Formation of meprobamate from carisoprodol is catalysed by CYP2C19. the blood level of glipizide rose.

Tobacco use. is a significant 1A2 inducer (Schrenk et al.Internal Medicine Case Vignettes 179 References Johnson JF. Dobmeier ME: Symptomatic hypoglycemia secondary to a glipizidetrimethoprim/sulfamethoxazole drug interaction. 2002 NIC FIT A 17-year-old male adolescent with asthma had nonetheless been smoking one pack of cigarettes each day. he decided to quit smoking “cold turkey. Curry TB. et al: Drug–drug interactions among elderly patients hospitalized for drug toxicity. and polyuria. DICP 24:250–251. In this situation. Pharmacogenetics 11:803– 808.5 µg/mL). He had been receiving theophylline (Theodur). respectively. and pediatrician. 2005 Wen X. With the cessation of smoking.4 µg/mL. sister. Moreover. JAMA 289:1652–1658. although his cravings eventually diminished somewhat. 2003 Kidd RS. Backman JT. Zevin and Benowitz 1999). these other symptoms seemed to worsen over the next several days. Wang JS. the pediatrician instructed the patient to take no theophylline for 24 hours and then to decrease his dosage to 600 mg/day thereafter. 1990 Juurlink DN. Mamdani M. Gallagher S.” He had been told about the intense nicotine cravings (nic fits) that people often experience when they abruptly stop smoking. This decrease in available 1A2 led to decreased metabolism of theophylline. After much encouragement from his parents. Drug Metab Dispos 30:631–635. 900 mg/day (blood level. but he also experienced palpitations. the patient’s available complement of 1A2 steadily decreased over the next several days. et al: Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Goldammer M. When it was discovered that his theophylline level had risen to 26. et al: Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9. 2001 Kirchheiner J. When he notified his pediatrician about his difficulties. Discussion This is an example of reversal of induction. Kopp A. restlessness. 16. occasional vomiting. she asked the patient to report to the laboratory in the morning for a theophylline level. Roots I. 1998. Clin Pharmacokinet 44:1209–1225. Theophylline is a substrate of P450 1A2 (Zhang and Kaminsky 1995). theophylline dosages typically need . via cigarette smoking. resulting in an increase in the blood level of theophylline and accompanying side effects even though there had been no increase in the theophylline dosage. et al: Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin.

about 1 month later the internist again prescribed fluoxetine. 10 mg/day. On this dosage. 0. she became acutely depressed. because her depression persisted. Ann Intern Med 106:553–555. and her levels remained in her normal range.125 mg/day. Morike K.4 ng/mL. 10 mg/day. 1998). Digoxin is a substrate of the P-glycoprotein transport protein (PauliMagnus et al. Because more digoxin was retained in enterocytes.125 mg/day. and her anorexia and confusion were returning. nicotine gum. Kaminsky LS: Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. the anorexia and confusion had remitted and the digoxin level had returned to normal. A digoxin level obtained at that time was 4. there was greater bioavailability and absorption of digoxin from the gut. the addition of fluoxetine significantly impaired the ability of the P-glycoprotein transporter to extrude digoxin from enterocytes back into the gut lumen. Jacob P 3rd: Cigarette abstinence. Discussion This is an example of an inhibitor added to a substrate. 1998 Zevin S. One week later. Biochem Pharmacol 50:205–211. 1987). 1987 Schrenk D. and theophylline disposition. Benowitz NL. The patient was restarted on digoxin. Clin Pharmacokinet 36:425–438. the patient developed significant anorexia and mild confusion. Within four days. her digoxin levels ranged from 1. Five days later. digoxin alone was eventually restarted. Her internist prescribed fluoxetine (Prozac). the digoxin level had risen to 2.2 ng/mL. Fluoxetine and digoxin were again discontinued. 1995 INOTROPIC ANOREXIA A 91-year-old female with known congestive heart failure (ejection fraction. Eur J Clin Pharmacol 53:361–367. Benowitz NL: Drug interactions with tobacco smoking: an update. 2001). leading to an increase in the .180 Drug–Drug Interaction Primer to be decreased by 25%–33% to compensate for the reversal of induction of 1A2 that results from smoking cessation (Lee et al. and a different antidepressant was chosen for a subsequent trial (Leibovitz et al. After the death of her grandson at the hands of a drunk driver. 1999 Zhang ZY. Brockmeier D.0 to 1. 0. Fluoxetine has been demonstrated to be an inhibitor of the P-glycoprotein transporter (Weiss et al. et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. Thus. The internist discontinued both the fluoxetine and the digoxin. References Lee BL.8 ng/mL. 20%) was stably maintained on digoxin (Lanoxin). 2003). However.

and paroxetine are all thought to moderately inhibit the P-glycoprotein transporter (Weiss et al. Bilchinsky T. 250 mg bid for 10 days. Discussion This is an example of an inhibitor added to a substrate. 1998). et al: Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther 305:197–204.1 ng/mL.5 ng/mL). held the patient’s digoxin for 2 days. References Leibovitz A. who diagnosed a community-acquired pneumonia and started the patient on clarithromycin (Biaxin). Naunyn Schmiedebergs Arch Pharmacol 363:337–343. 20 mg/day (Spier and Frontera 1991). alpha-methyldigoxin and beta-acetyldigoxin. the blurry-vision complaint led the physician to send the patient to the laboratory for a digoxin level. When he reported these symptoms to his internist. 0. Within 5 days. Digoxin is a substrate of the P-glycoprotein transport pump (PauliMagnus et al. and blurry vision. which had risen to 2. Frontera MA: Unexpected deaths in depressed medical inpatients treated with fluoxetine. Although drug interactions resulting purely from alterations in the functioning of the P-glycoprotein transporter are relatively infrequent. Fluoxetine. Dormann SM.125 mg/day (blood level. The internist discontinued the clarithromycin. et al: Elevated serum digoxin level associated with coadministered fluoxetine. lethargy. he developed a progressive cough. Godel A. the patient experienced new-onset nausea. One winter. He visited his internist. then started a trial of moxifloxacin (Avelox). 2001 Spier SA. 2003 COMMUNITY-ACQUIRED TOXICITY A 72-year-old male with congestive heart failure was taking digoxin (Lanoxin). this factor is probably underestimated in both frequency and severity as a meaningful contributor to clinically significant drug interactions. 2001). She died abruptly and unexpectedly several days after starting fluoxetine. At her regular dosage. she had a digoxin blood level of 2. sertraline. Another series of three patients who died unexpectedly within 10 days of starting fluoxetine included one case in which a 55-year-old female with congestive heart failure and atrial fibrillation received digoxin. Ann Intern Med 158:1152–1153. J Clin Psychiatry 52:377–382. 1998 Pauli-Magnus C. 1991 Weiss J. and a persistent low-grade fever.Internal Medicine Case Vignettes 181 blood level of digoxin (Leibovitz et al. vomiting. Murdter T. et al: P-glycoprotein–mediated transport of digitoxin.9. Clarithromycin has been demonstrated to be an inhib- . 2003). Martin-Facklam M. fluvoxamine. which was effective and which the patient tolerated without difficulty. Gil I. 1.

1998). the addition of clarithromycin significantly impaired the ability of the P-glycoprotein transporter to extrude digoxin from enterocytes back into the gut lumen. because this was the primary “statin” on the clinic formulary. Neuvonen et al. The internist consulted with the hospital pharmacist. 40 mg/day. Hui CS. et al: Drug-drug interactions among elderly patients hospitalized for drug toxicity. et al: Reversal of anticancer drug resistance by macrolide antibiotics in vitro and in vivo. specifically . et al: Effect of clarithromycin on steady-state digoxin concentrations. Murdter T. References Juurlink DN. Clin Exp Pharmacol Physiol 27:587–593. Kitaichi K. 2000). which lowered his cholesterol to 212 mg/dL. Mamdani M. 2001 Tanaka H. his dosage was titrated to the maximum recommended dosage of 80 mg/day. he was told that he should start taking a medication for his hypercholesterolemia (285 mg/dL). there was a more than 12-fold greater likelihood of exposure to clarithromycin in the week prior to admission. Ann Pharmacother 37:178–181. et al: P-glycoprotein–mediated transport of digitoxin. 2003). leading to an increase in the blood level of digoxin (Tanaka et al. who suggested a switch from simvastatin to pravastatin (Pravachol). Because more digoxin was retained in enterocytes. He was prescribed simvastatin (Zocor). Ueno K. Over the succeeding months. 2003 Wang L. Carbamazepine is an inducer of multiple P450 enzymes. Godel A. 800 mg/day. alpha-methyldigoxin and beta-acetyldigoxin. 2000 FORMULARIES A 68-year-old male had received carbamazepine. there was greater bioavailability and absorption of digoxin from the gut. 1999. Kopp A.182 Drug–Drug Interaction Primer itor of the P-glycoprotein transporter (Wang et al. JAMA 289:1652–1658. A study by Juurlink et al. During a visit to his Veterans Administration clinic. and even at that dosage his cholesterol decreased only modestly (262 mg/dL). 2003 Pauli-Magnus C. 20 mg/day. (2003) demonstrated that in patients older than 66 years who were treated with digoxin and hospitalized due to digoxin toxicity. Thus. Matsumoto K. Simvastatin is a substrate of P450 3A4 (Gruer et al. Discussion This is an example of a substrate added to an inducer. Naunyn Schmiedebergs Arch Pharmacol 363:337–343. for the past 20 years for treatment of a longstanding partial complex seizure disorder.

so he decided to give this a try as well. 40 mg/day. Kivisto KT: Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacokinet 39:397–412. et al: Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. a greater-than-normal amount of 3A4 was available to metabolize the simvastatin as a result of chronic 3A4 induction by carbamazepine. He took the St. it had risen to 245 mg/dL. leading him to experience dysphoria. and decreased concentration. Mercuri MF. 2004). anhedonia. Am J Cardiol 84:811–815. Clin Pharmacol Ther 63:332–341. Molloy M. He consulted his internist. a statin whose metabolism is not appreciably induced by carbamazepine because it does not undergo significant oxidative metabolism through the P450 system (Hatanaka 2000). although his wife’s condition was also improving during that time. 1998 Spina E. After 1 month. Ucar et al. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. Thus. his symptoms improved somewhat. 1996 Ucar M. . His wife then was hospitalized with a broken hip after a fall. However. Neuvonen M. decreased energy. John’s wort per a local pharmacist’s instructions.Internal Medicine Case Vignettes 183 including 3A4 (Arana et al. Thus. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. References Arana GW. 1996. Spina et al. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Epstein S. 1988. which resulted in his cholesterol again dropping below 200 mg/dL. He had a friend who had responded well to St. Kantola T. Vega JM. the next time that the patient had his cholesterol checked. 2000 Neuvonen PJ. 2004 HYPERICUM AND HYPERCHOLESTEROLEMIA A 71-year-old male had maintained good control (<200 mg/dL) of his cholesterol while taking simvastatin (Zocor). 1988 Gruer PJ. One study demonstrated that coadministration of carbamazepine and simvastatin yielded simvastatin levels that were 75% less than in the absence of carbamazepine (Ucar et al. John’s wort (Hypericum perforatum). J Clin Psychiatry 49:448–449. Luurila H. Pisani F. who increased the simvastatin dosage to 80 mg/day. The hospital pharmacist circumvented this problem by recommending pravastatin. 2004). Eur J Clin Pharmacol 59:879– 882. 1999 Hatanaka T: Clinical pharmacokinetics of pravastatin: mechanisms of pharmacokinetic events. Clin Pharmacokinet 31:198–214. the presence of the carbamazepine rendered even the recommended maximum dosage of simvastatin much less effective in lowering the patient’s cholesterol.

When St. 1999 Markowitz JS. Kantola T.1. He arranged for her to obtain a prothrombin time. Roby et al. Ohmori M. et al: Different effects of St John’s wort on the pharmacokinetics of simvastatin and pravastatin. . 1999. Two weeks later. thus restoring cholesterol-lowering efficacy. 2001 CHOLESTEROL AND COAGULATION A 63-year-old female had received warfarin (Coumadin). Kantor E. One study demonstrated that the simvastatin area under the curve decreased by roughly 50% after the addition of St. The internist (inadvertently) compensated for this effect by doubling the simvastatin dosage. 1998 Roby CA. et al: Effect of St John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. and the INR had risen to 4. Kivisto KT: Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. et al: St. 2001). Tsuruoka S. 2000). 2. Am J Cardiol 84:811–815. so she promptly reported this event to her internist. The internist promptly discontinued the fluvastatin and replaced it with pravastatin (Pravachol). Within 2 weeks. 2000 Sugimoto K. References Gruer PJ. Neuvonen et al. She did not feel she had struck the door frame especially hard. her cholesterol had recently increased to 272 mg/dL. John’s wort was added to the simvastatin. Clin Pharmacol Ther 63:332–341. Clin Pharmacol Ther 70:518– 524. JAMA 290:1500–1504. resulting in a decrease in the blood level of simvastatin and loss of efficacy as a cholesterol-lowering agent. Mercuri MF. Vega JM. her INR had returned to the normal range. a large bruise appeared. John’s wort (Sugimoto et al. John’s wort is an inducer of 3A4 (Markowitz et al. St. Clin Pharmacol Ther 67:451–457. 40 mg bid. 2003. et al: Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. DeVane CL. Anderson GD. after accidentally hitting her arm against a door frame. Her internist noted that despite dietary interventions. Simvastatin is a substrate of P450 3A4 (Gruer et al.6) as anticoagulant treatment for chronic atrial fibrillation. 1998). even though the dosage had not been decreased. Donovan JL. this led to a significant increase in the amount of 3A4 available to metabolize the simvastatin. so he added fluvastatin (Lescol). John’s wort: effect on CYP3A4 activity. 2003 Neuvonen PJ.184 Drug–Drug Interaction Primer Discussion This is an example of an inducer added to a substrate. 5 mg/day (international normalized ratio [INR].

Internal Medicine Case Vignettes 185 Discussion This is an example of an inhibitor added to a substrate. 1996 . Ann Pharmacother 30:1399–1402. Mol Diagn 4:365–379. rose even though the warfarin dosage had not been increased (Andrus 2004. et al: The mechanism of the warfarin–rifampin drug interaction. 1996). Warfarin’s metabolism is very complex. 2001 Trilli LE. References Andrus MR: Oral anticoagulant drug interactions with statins: case report of fluvastatin and review of the literature. 1999 Scripture CD. Pieper JA: Clinical pharmacokinetics of fluvastatin. Valdes R Jr: Pharmacogenetics in the practice of laboratory medicine. The addition of the fluvastatin led to a significant impairment in the ability of 2C9 to efficiently metabolize the warfarin. which does not inhibit the metabolism of warfarin. 2004 Heimark LD. The internist corrected this problem by switching to pravastatin. Clin Pharmacol Ther 42:388–394. 1987 Linder MW. Pharmacotherapy 24:285–290. The more active S-warfarin isomer is metabolized primarily by P450 2C9 (Heimark et al. Trilli et al. Trager WF. leading to the increased likelihood of bruising. Fluconazole is a known inhibitor of P450 2C9 (Scripture and Pieper 2001). Aspinall SL. Gibaldi M. and correspondingly the INR. et al: Potential interaction between warfarin and fluvastatin. Linder and Valdes 1999). Clin Pharmacokinet 40:263–281. Kelley CL. 1987. the blood level of warfarin. Consequently.

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The quetiapine dosage was increased to 800 mg/day. 600 mg/day. he experienced several tonic-clonic seizures. However. During the recovery period. The P450-savvy inpatient psychiatrist switched the patient from quetiapine to ziprasidone (Geodon). These seizures prompted the consulting neurologist to have him start taking phenytoin (Dilantin). in subsequent weeks. 300 mg/day. he began to grow more flagrantly paranoid. He became fearful of sleeping because of the belief that the staff would “experiment” on him while he slept. His seizure activity was rapidly brought under control with the phenytoin. and his delusions remitted within another 3 weeks. He also refused to eat or drink anything that he had not opened himself.Chapter 4 NEUROLOGY CASE VIGNETTES PARANOIA A 28-year-old construction worker with schizophrenia had done quite well for the past 2 years on a regimen of quetiapine (Seroquel). The patient tolerated the medication at this dosage without difficulty. Finally. He was then transitioned to a rehabilitation facility. he was transferred to an inpatient psychiatric facility. One day. titrating to a dosage of 160 mg/day. but this did not halt the progression of his paranoid delusions. after barricading himself in his room and becoming acutely threatening. he fell from a scaffold and suffered significant closed head injury. 187 .

and over the next 3 weeks the methadone dosage was tapered back to 50 mg/day. References DeVane CL. J Clin Psychopharmacol 21:89–93. over the next several weeks. the patient developed typical symptoms of opioid withdrawal (muscle cramping. and phenytoin is an inducer of multiple P450 enzymes. and insomnia). 2002 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Yeh C. . However. Hence. Quetiapine is primarily a 3A4 substrate. he developed trigeminal neuralgia. nausea. to which the neuralgia promptly responded. the psychiatrist increased the dosage of the patient’s methadone to 80 mg/day and prevailed on his neurologist colleague to change the carbamazepine to gabapentin (Neurontin). the increase in dosage of quetiapine from 600 mg/day to 800 mg/day was not able to compensate for this effect. Drug Metab Dispos 31:533–539. with a minor contribution from 2D6 (DeVane and Nemeroff 2001). Studies indicate that this interaction can increase the clearance of quetiapine fivefold (Wong et al. Toxicology 181–182:199–202. The addition of the phenytoin led to an increase in the amount of 3A4 available to metabolize the quetiapine. The significant decrease in quetiapine blood level that ensued over the course of several weeks led to the emergence of paranoid delusions and accompanying problematic behaviors. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. and a consulting neurologist prescribed carbamazepine (Tegretol). 2003 Wong YW. piloerection. resulting in significantly more rapid metabolism of quetiapine. 600 mg/day. el-Sankary W. 2001 Gibson GG. While taking this regimen.188 Drug–Drug Interaction Primer Discussion This is an example of an inducer added to a substrate. diarrhea. Nemeroff CB: Clinical pharmacokinetics of quetiapine: an atypical antipsychotic. Clin Pharmacokinet 40:509–522. After reviewing the patient’s history. with no further adverse effects. Thyrum PT: The effects of concomitant phenytoin administration on the steady-state pharmacokinetics of quetiapine. 2002. The clinic psychiatrist was consulted. His regular dosage of methadone (Dolophine) was 50 mg/day. The patient’s withdrawal was ameliorated by the increase in methadone dosage. specifically including 3A4 (Gibson et al. 2001 GRADUAL WITHDRAWAL (I) A 25-year-old man with a history of opioid dependence had been enrolled in a methadone maintenance program for the past 2 years. Raucy 2003). 2001). This led to a sharp decrease in the blood level of quetiapine.

This explains the need to gradually taper back to the original methadone dosage over the 2–3 weeks following the discontinuation of carbamazepine. Spina et al. Discontinuation of the carbamazepine halted the increased production of 3A4. Bowron P. Pisani F. 2 mg bid. Chem Res Toxicol 9:365–373. there was an increased production of 3A4 over the ensuing weeks. more 3A4 was available to metabolize the methadone. He then developed a seizure disorder. titrated to a dosage of 300 mg bid (blood level. References Arana GW. lip smacking. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. [1988]) in the blood level of methadone over that time. Ucar et al. This decrease in blood level led to an emerging opioid withdrawal syndrome and the need for an acute methadone dosage increase to address this. Molloy M. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. according to Bell et al. and risperidone (Risperdal). et al: Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. et al: The use of serum methadone levels in patients receiving methadone maintenance. specifically including 3A4 (Arana et al. and a neurologist started him on carbamazepine. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid.2 µg/mL). Neuvonen M. the patient developed new perioral dyskinesias (tongue thrusting. Eur J Clin Pharmacol 59:879– 882. 1996. However. Seres V. 1996 Ucar M. 1988 Iribarne C. Berthou F. Baird S. Clin Pharmacol Ther 43:623–629. Clin Pharmacokinet 31:198–214. With the addition of the carbamazepine to the patient’s regimen. 1996 Spina E. 8. 1988. J Clin Psychiatry 49:448–449. 20 mg bid. Methadone is a 3A4 substrate (Iribarne et al. lip puckering) that . 1988 Bell J. and carbamazepine is an inducer of multiple P450 enzymes. 1996). resulting in a decrease (approximately 60%. 2004 DYSKINESIAS A 14-year-old diagnosed with comorbid attention-deficit/hyperactivity disorder and Tourette’s disorder was being successfully managed with methylphenidate (Ritalin SR). Within 2 weeks of starting the carbamazepine. 2004). Thus.Neurology Case Vignettes 189 Discussion This is an example of an inducer added to a substrate. Epstein S. it takes weeks for the previously produced “extra” 3A4 to “die off” and for levels of 3A4 to return to baseline. Luurila H.

Oesterheld. Spina et al. Just as the presence of carbamazepine led to a gradual increase in the amount of 3A4. References Arana GW. Spina et al. Epstein S. The dyskinesias persisted for roughly 10 days but then eventually remitted (J. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. Clin Pharmacokinet 31:198–214. The patient’s carbamazepine was then discontinued. et al: Plasma concentrations of risperidone and 9hydroxyrisperidone: effect of comedication with carbamazepine or valproate. personal communication. and he was started on divalproex sodium (Depakote). 2004). 1997 DeVane CL. resulting in a rise in the blood level of risperidone and a subsequent remission of the dyskinesias. 2002. The addition of carbamazepine led to a gradual increase in the production of 3A4 and therefore the amount of that enzyme available to metabolize the risperidone. May 2002).to threefold decrease in the blood level of risperidone (deLeon and Bork 1997. Ono et al. Avenoso A. Ucar et al. Eur J Clin Pharmacol 59:879– 882. 2002 Spina E. Neuvonen M. J Clin Psychiatry 58:450. 2000 Ucar M. Nemeroff CB: An evaluation of risperidone drug interactions. it took 1–2 weeks following the discontinuation of the carbamazepine before that “extra” 3A4 was no longer metabolically available and the amount of active 3A4 returned to baseline levels. Risperidone is a substrate of 2D6 and 3A4 (DeVane and Nemeroff 2001). Bork J: Risperidone and cytochrome P450 3A. 2004 . Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. 2001 Ono S.190 Drug–Drug Interaction Primer were quite distinct from his Tourette’s-related motor tics.R. this resulted in an acute two. 1988 deLeon J. Mihara K. 1988. 2000) and the subsequent emergence of withdrawal dyskinesias. Over the span of 2 weeks. Luurila H. Facciola G. Suzuki A. Molloy M. It is also likely that the methylphenidate contributed to the development of the dyskinesias on a pharmacodynamic level. J Clin Psychiatry 49:448–449. Ther Drug Monit 22:481–485. Psychopharmacology (Berl) 162:50–54. and carbamazepine is an inducer of multiple P450 enzymes. specifically including 3A4 (Arana et al. Pisani F. 1996. 1996 Spina E. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. Discussion This is an example of an inducer added to a substrate. et al: Significant pharmacokinetic interaction between risperidone and carbamazepine: its relationship with CYP2D6 genotypes. J Clin Psychopharmacol 21:408–416.

However. it has been demonstrated that oxcarbazepine is capable of sufficient 3A4 induction to increase 3A4’s efficiency in metabolizing ethinylestradiol to the point that ethinylestradiol-containing oral contraceptives significantly lose their efficacy (Elwes and Binnie 1996. It is generally true that the increases in 3A4 induced by oxcarbazepine do not tend to exert clinically significant effects on most 3A4 substrates. vigabatrin. partly because of the neurologist’s belief that oxcarbazepine did not significantly induce the metabolism of other medications as carbamazepine did. Life Sci 47:1981– 1988.R. albeit not as powerful an inducer as carbamazepine. However. Jurgens U: Influence of oxcarbazepine and methsuximide on lamotrigine concentrations in epileptic patients with and without valproic acid comedication: results of a retrospective study. 1999 . and oxcarbazepine is a 3A4 inducer (Wilbur and Ensom 2000). 1996 Fattore C. Epilepsia 40:783–787. Oesterheld. Its ability to interact with other medications is not restricted to its induction of 3A4 (May et al. they decided on a trial of oxcarbazepine (Trileptal). Much to her surprise. personal communication. After discussing the risks and benefits of various agents. As with several other anticonvulsants. Fattore et al.Neurology Case Vignettes 191 UNPLANNED PARENTHOOD A 35-year-old married woman with a seizure disorder had remained seizurefree for 5 years while taking carbamazepine (Tegretol). Clin Pharmacokinet 30:403–415. 1999 Guengerich FP: Metabolism of 17 α-ethynylestradiol in humans. 1999). Binnie CD: Clinical pharmacokinetics of newer antiepileptic drugs: lamotrigine. et al: Induction of ethinylestradiol and levonorgestrel metabolism by oxcarbazepine in healthy women. Gatti G. 1990 May TW. oxcarbazepine induces the glucuronidation of many other medications. She transitioned to oxcarbazepine without incident and then began an oral contraceptive that contained ethinylestradiol as the active ingredient. References Elwes RD. May 2002). Cipolla G. Discussion This is an example of a substrate added to an inducer. Ther Drug Monit 21:175–181. so she consulted with her neurologist. gabapentin and oxcarbazepine. Ethinylestradiol is a 3A4 substrate (Guengerich 1990). Rambeck B. she was hoping to begin taking oral contraceptive medication. 1999). she was pregnant within the next year (J.

325 mg/day. 2002. he experienced more fatigue than he had expected. the ability of 3A4 . however. Fearing another TIA. Because he had not had any seizures for more than 20 years. which reliably produced blood levels between 7 and 10 µg/mL. His subsequent evaluation revealed significant hypertension (190/115 mm Hg). and indeed he was seizure-free for another 4 years while taking no antiepileptic medication. his carbamazepine was titrated back to this dosage. In the past 4 years. 1996. 2B6. Unfortunately. he then had another seizure. 2004). the patient and his neurologist decided that he could try to discontinue the carbamazepine. 2C9. However. However. Spina et al. there was some doubt as to whether he truly had an idiopathic seizure disorder or whether his seizures had resulted solely from prior episodes of alcohol withdrawal. Over the course of 2 weeks. and phase II metabolism (UGT2B7) making minor contributions to carbamazepine’s metabolism (Pearce et al. His blood level was found to be 17. Diltiazem is a competitive inhibitor of 3A4 (Sutton et al. Staines et al. Discussion This is an example of a substrate added to an inhibitor. which he initially tolerated without difficulty. and when he woke up the next morning his speech was slurred. and he was placed on diltiazem (Cardizem SR). his resulting blood pressure was 135/90 mm Hg. However. and aspirin. and an ambulance transported him to the nearest emergency room.192 Drug–Drug Interaction Primer Wilbur K. Once there. Carbamazepine was titrated to a dosage that had produced a particular blood level in the past. His prior dosage of carbamazepine had been 800 mg/day. now that diltiazem was present. and he and his neurologist decided that he should restart the carbamazepine. 2C8. 2E1. by day 4 at this dosage of carbamazepine. As a result of the diltiazem. the patient did experience a transient ischemic attack (TIA) in which his initial symptom was slurred speech. he promptly called 911. with 1A2.3 µg/mL. and a computed tomography scan of the brain was negative. his neurologist evaluated him and ordered a carbamazepine blood level. 1997). Clin Pharmacokinet 38:355–365. His neurologist concluded that his slurred speech had been a result of mild carbamazepine toxicity and not another TIA. 2000 FALSE ALARM A 67-year-old man with a diagnosed seizure disorder had been successfully treated with carbamazepine in the past. Carbamazepine is primarily a 3A4 substrate. Ensom MH: Pharmacokinetic drug interactions between oral contraceptives and second-generation anticonvulsants. 180 mg bid.

she felt that her pulse was racing. the effect of diltiazem inhibition of 3A4 was maximal. 7. et al: Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. References Gadde K. Calabrese JR: Diltiazem effect on carbamazepine levels in manic depression. The addition of diltiazem to carbamazepine typically leads to carbamazepine blood level increases as high as 85% (Gadde and Calabrese 1990). the presence of this “new” 3A4 inhibition resulted in a greater blood level of carbamazepine than when the patient had taken this dosage of carbamazepine in the past. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. 1996 Staines AG. 2002 Spina E. However. Burchell B: N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. over the next week the patient experienced increasing anxiety and a return of her panic attacks. Vakkalagadda GR. and she experienced tremulousness and agitation. Butler AM. 1990 Pearce RE. J Clin Psychopharmacol 10:378–379. Coughtrie MW. Pisani F. 1997 GRADUAL WITHDRAWAL (II) A 19-year-old woman with panic disorder was responding well to alprazolam (Xanax). Her mother also had a chronic seizure disorder and had done quite well while taking carbamazepine (Tegretol). J Pharmacol Exp Ther 282:294–300. and she was referred to a neurologist. which the patient tolerated without difficulty.and 3-hydroxylated metabolites. Because the activity of 1A2 and 2C9 was not sufficient to compensate for this effect. Nadin L. She then experienced her first seizure.Neurology Case Vignettes 193 to contribute to the efficient metabolism of carbamazepine was impaired. The carbamazepine was titrated to a dosage of 800 mg/day (blood level. Leeder JS: Pathways of carbamazepine bioactivation in vitro. who . Additionally. 2004 Sutton D. but the counterbalancing effect of carbamazepine autoinduction had not yet reached its maximal ability to generate a lower baseline blood level. I: Characterization of human cytochromes P450 responsible for the formation of 2. Clin Pharmacokinet 31:198–214. because full carbamazepine autoinduction was not likely to have occurred after 2 weeks of administration. Also. dispensed by her internist. Drug Metab Dispos 30:1170–1179. She reported her difficulties to her internist. and she agreed. J Pharmacol Exp Ther 311:1131–1137. The resulting state of mild carbamazepine toxicity accounted for the patient’s fatigue and slurred speech. 1 mg tid.7 µg/mL) over a 2-week period. The neurologist suggested that the patient also start taking carbamazepine.

1988) to the extent that the patient actually entered into a state of mild benzodiazepine withdrawal. 2000). She was given lorazepam (Ativan). 2 mg po. Spina et al. he recovered fully from the sequelae of his fall. Epstein S. During the recovery period. 2004 CHOLESTEROL 451 A 58-year-old man with severe hypercholesterolemia had maintained a total cholesterol level of less than 250 mg/dL by taking atorvastatin (Lipitor). et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. and a prescription for 1 mg qid. Over the next month. and carbamazepine is an inducer of multiple P450 enzymes. Discussion This is an example of an inducer added to a substrate. specifically including 3A4 (Arana et al. This resulted in a decrease in the blood level of alprazolam (Arana et al. Neuvonen M. 1996 Ucar M. J Clin Psychiatry 49:448– 449. 1996. Clin Pharmacokinet 38:41–57. with instructions to discontinue her alprazolam and to contact her internist immediately if any of these symptoms should recur. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. a benzodiazepine that does not rely on P450 enzymes for its metabolism and that also is not affected by carbamazepine’s ability to induce specific glucuronidation enzymes. Luurila H. although he remained on the phenytoin for . and her blood pressure was 150/95 mm Hg. Alprazolam is a 3A4 substrate (Dresser et al. Ucar et al. Molloy M.194 Drug–Drug Interaction Primer told her to report to the nearest emergency room. References Arana GW. he experienced a seizure and was placed on phenytoin (Dilantin) at a therapeutic dosage. Eur J Clin Pharmacol 59:879– 882. Pisani F. Her heart rate was found to be 116 beats per minute. 1988 Dresser GK. The addition of the carbamazepine led to an increase in the amount of 3A4 that was available to metabolize the alprazolam. The astute emergency room physician addressed this difficulty by changing from alprazolam to lorazepam. He then fell from a ladder and suffered a closed head injury. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. Spence JD. 2004). stat. Clin Pharmacokinet 31:198–214. 2000 Spina E. 1988.

Murphy and Dominiczak 1999). he was crossed over from the phenytoin to divalproex sodium (Depakote). which led to a significant increase in the serum cholesterol level. Drug Metab Dispos 31:533–539. his cholesterol level had risen to 451 mg/dL. 16. 2002 Khandwala HM: Lipid lowering inefficiency of high-dose statin therapy due to concurrent use of phenytoin. In the weeks during which the phenytoin was tapered. the patient experienced increasing sedation and incoordination. Dominiczak MH: Efficacy of statin therapy: possible effect of phenytoin. 1999 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. After consulting with his neurologist. Toxicology 181–182:199–202. Raucy 2003).3 µg/mL). 80 mg/day. the psychiatrist at the methadone clinic decreased . Atorvastatin is a 3A4 substrate (Beaird 2000). 2006 Murphy MJ. from the methadone clinic at which he was enrolled. Within 3 days of the discontinuation of the phenytoin. 2000 Gibson GG. 2002. el-Sankary W. South Med J 99:1385–1387. The addition of phenytoin led to increased production of 3A4 and thus more efficient metabolism of the atorvastatin. even though the dosage had not been changed (Khandwala 2006. but he began to develop gum hyperplasia and enlargement of his lips. This lower blood level of atorvastatin rendered it significantly less effective as a cholesterol-lowering agent via HMG-CoA (3-hydroxy-3-methylglutaryl– coenzyme A) reductase inhibition. After some discussion. He had been doing well. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. and methadone (Dolophine). This resulted in a decrease in the blood level of atorvastatin. J Am Pharm Assoc 40:637–644. Postgrad Med J 75:359–360. Discussion This is an example of an inducer added to a substrate. specifically including 3A4 (Gibson et al. and phenytoin is an inducer of multiple P450 enzymes. he felt frankly “high” and reported this to his neurologist and his counselor at the methadone clinic. During his next routine visit with his internist. 2003 ANTICONVULSANT WITHDRAWAL INTOXICATION A 28-year-old man with a history of opioid dependence and a seizure disorder was receiving phenytoin (Dilantin) from his neurologist. 400 mg/day (blood level.Neurology Case Vignettes 195 seizure prophylaxis. References Beaird SL: HMG-CoA reductase inhibitors: assessing differences in drug interactions and safety profiles.

Raucy 2003). 1999. with the taper and discontinuation of the phenytoin. which increased the amount of 3A4 that was available to metabolize the methadone. Thus. Gibson et al. 1996). Ther Drug Monit 21:171–174. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. Drug Metab Dispos 31:533–539. Toxicology 181–182:199–202. 2002 Iribarne C. Stahle L: Lamotrigine drug interactions in a TDM material. el-Sankary W. et al: Phenytoin-induced methadone withdrawal. Pond SM. 300 mg/day (blood levels generally around 16 µg/mL). 2002. for the past 5 years. 3A4. The clinic psychiatrist compensated for this reversal of induction by halving the methadone dosage. Berthou F. The original appropriate dosage of methadone was influenced by the presence of the phenytoin. This led to an increase in the blood level of methadone. Chem Res Toxicol 9:365–373. the amount of 3A4 decreased over the succeeding 2–3 weeks. which provided therapeutic efficacy and a remission of intoxication. 1999 Chetty M. Kreek MJ. she awoke with tingling on . Chetty et al. 1996 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. specifically including 2C9. Ther Drug Monit 20:60–62. 1998.196 Drug–Drug Interaction Primer his methadone dosage to 40 mg/day. 2C19. 2003 Tong TG. 1981 CLOTS A 45-year-old woman with a seizure disorder had been successfully treated with phenytoin (Dilantin). References Bottiger Y. Baird S. Ann Intern Med 94:349–351. This necessitated a higher dosage of methadone than would have been needed if the phenytoin had not been present (Tong et al. et al: Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Methadone is a substrate of 3A4 (Iribarne et al. Seymour MA: Phenytoin auto-induction. and uridine 5′-diphosphate glucuronosyltransferase 1A4 (Bottiger et al. even though the methadone dosage had not been increased. Miller R. which provided relief from his cravings and a cessation of his intoxicated state. which returned 3A4 to its lower baseline level of activity. Discussion This is an example of reversal of induction. One morning. 1981). Svensson JO. and phenytoin is an inducer of multiple enzymes. 1998 Gibson GG.

the patient was severely somnolent. and migraine headaches had been receiving 150 mg/day of imipramine (Tofranil) (imipramine + desipramine blood level roughly 250 ng/mL) for the past 3 years. over the past 6 months her migraines had become more frequent and severe. 1999 Ko JW. even though the phenytoin dosage had not been increased.Neurology Case Vignettes 197 the right side of her face. Because 2C9 was not able to compensate for ticlopidine’s strong 2C19 inhibition. The treating physician decided to start the patient on ticlopidine (Ticlid). but her phenytoin blood level was 39. This resulted in a state of clinical phenytoin toxicity. and ticlopidine is a strong inhibitor of 2C19 (Ko et al.0 µg/mL (Donahue et al. Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. Clin Pharmacol Ther 66:563–568. 250 mg bid. Rodriguez-Barradas MC. Discussion This is an example of an inhibitor added to a substrate. Ieiri I. 1994. However. 1994 Donahue S. References Cadle RM. et al: The effects of genetic polymorphism of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. or engaging in any behavior that might make it difficult for her to obtain . Within 1 week. Epilepsia 39:1317–1323. the addition of ticlopidine significantly impaired the ability of 2C19 to contribute to the metabolism of phenytoin. 1998). Ann Pharmacother 28:191–195. Flockhart DA. dizzy. 2000 Mamiya K. in remission. This had led her to become very tentative about taking trips. Mamiya et al. et al: Fluconazole-induced symptomatic phenytoin toxicity. 2000). and nauseated with vomiting. and her speech was slightly slurred. 1999). Desta Z. Her computed tomography scan was unremarkable. Br J Clin Pharmacol 49:343–351. Abernathy DR: Ticlopidine inhibits phenytoin clearance. Zenon GJ 3rd. Shimamoto J. She was taken to a local emergency room and eventually diagnosed with a transient ischemic attack. Fearing a full stroke. et al: In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6. Soukhova NV. there was an increase in the blood level of phenytoin. Thus. 1998 RUMINATION A 27-year-old woman with a history of polysubstance abuse. making evening plans. she called 911 and was again transported to the emergency room. with generally good results.

He had the patient begin taking fluvoxamine. while the functioning of the principal enzyme responsible for desipramine’s metabolism (2D6) continued to function virtually at its baseline level of activity. Although 2D6 was able to contribute to imipramine’s metabolism. This . After 2 days on this dosage. von Moltke et al. so he wanted to avoid any such medications. and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. he was impressed by the strength of the patient’s anxious ruminations about her migraine pain. The patient and her neurologist had been reluctant to prescribe any controlled substances. constipation. Although her electrocardiogram revealed only sinus tachycardia. the patient reported light-headedness. at a dosage of 50 mg/day. and he wondered if her secondary anxiety might not be compounding her pain. where her imipramine + desipramine blood level was found to be 973 ng/mL. the neurologist wisely advised her to report to the nearest emergency room. blurry vision. Fearing the worst. Given her persistent ruminations. 1995). the addition of fluvoxamine significantly impaired the ability of these enzymes to make an effective contribution to the metabolism of imipramine. 1999). He had also heard that fluvoxamine (Luvox) was especially helpful for obsessive-compulsive disorder. the inhibition of all the other pertinent P450 enzymes clearly overwhelmed 2D6’s capabilities. and 1A2 (Yang et al. Although a breakdown of the individual imipramine + desipramine blood levels was not available from this emergency room. 2C9. During her most recent visit to her neurologist.198 Drug–Drug Interaction Primer emergent relief from her migraine pain. it would stand to reason that the imipramine portion of the sum would be greatly elevated while the desipramine portion might be unaffected or minimally elevated. he thought fluvoxamine would be a good choice. 1993). Niemi et al. Studies have demonstrated that the addition of fluvoxamine to imipramine can cause a more than threefold increase in blood levels (Spina et al. and the blood level of imipramine + desipramine (imipramine’s primary metabolite) rose nonetheless. Discussion This is an example of an inhibitor added to a substrate. and titrated the dosage to 150 mg/day over 10 days. Fluvoxamine is a strong inhibitor of 1A2. 2001. This would be due to the inhibition of 3A4 and 2C19 impairing the conversion of imipramine into desipramine via demethylation. given the patient’s history of addiction. Imipramine is a tertiary-amine tricyclic antidepressant whose metabolism depends most on the intact functioning of 2C19. sedation. 3A4. and palpitations. she was nonetheless admitted to a telemetry unit for observation. 2D6. The neurologist had heard that 2D6 inhibitors could elevate tricyclic antidepressant blood levels. Thus. 2002.

the patient was again consistently enuretic at night.8 µg/mL). Sai Y. Backman JT. J Clin Psychopharmacol 15:125–131. 2D6. 1988. responded to a trial of imipramine (Tofranil). Parker et al. Clin Pharmacol Ther 71:141–152. 2001 Spina E. 2B6. Spina et al. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. 2004. et al: Eight inhibitory monoclonal antibodies define the role of individual P450s in human liver microsomal diazepam. et al: Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects. 2002 Niemi M. Avenoso A. 2C9. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. References Christensen M.Neurology Case Vignettes 199 pattern would be analogous to those seen in the cases of clomipramine added to fluvoxamine (see “Symmetry” in Chapter 2) and nefazodone added to amitriptyline (see “Vigilance Always” in Chapter 2). to address his newonset seizure disorder. Mihara K. 6. 1998. Drug Metab Dispos 27:102–109. 3A4. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Greenblatt DJ. Faucette et al. 1996. Court MH. which had not responded to behavioral interventions. His parents were awaiting a consultation with a pediatric urologist when the patient experienced a seizure. 1999 ENURESIS (II) A 10-year-old boy with persistent nocturnal enuresis. in addition to his imipramine. 1995 Yang TJ. 7-ethoxycoumarin. Clin Pharmacol Ther 69:194–200. Miners and Birkett 1998. Tybring G. 1999). He was eventually placed on carbamazepine (Tegretol). Discussion This is an example of an inducer added to a substrate. Within 2 weeks. and 3A4 (Arana et al. 1993 von Moltke LL. Neuvonen M. . Imipramine is a tertiary-amine tricyclic antidepressant whose metabolism depends most on the intact functioning of 2C19. and imipramine metabolism. Pollicino AM. Krausz KW. Carbamazepine is an inducer of multiple P450 enzymes. 600 mg/day (blood level. specifically including 1A2. and 1A2 (Yang et al. 50 mg/day (no blood levels were obtained). Ther Drug Monit 15:243–246.

but care would have to be taken to reduce the imipramine dosage if the carbamazepine were ever removed. et al: Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test. Because the efficacy of imipramine for nocturnal enuresis presumably relies on its dose-dependent (and therefore blood level–dependent) anticholinergic properties. Pritchard P. Molloy M. et al: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Sai Y. Birkett DJ: Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Thus. Preston T. 1990). 1999 THE MATRIX A 26-year-old man with schizophrenia was being stably maintained on haloperidol (Haldol). Drug Metab Dispos 27:102–109. Pisani F. and his neurologist had him start tak- . 2004 Miners JO. 10 mg/day. and imipramine metabolism. 1998 Spina E. et al: Eight inhibitory monoclonal antibodies define the role of individual P450s in human liver microsomal diazepam. He then developed a seizure disorder. the addition of carbamazepine led to increased amounts of 3A4 and 1A2 that were available to metabolize the imipramine at a more rapid rate. Therapeutic efficacy could be recaptured by increasing the imipramine dosage to compensate for carbamazepine’s induction of imipramine’s metabolism. 2004 Yang TJ. Tricyclic levels should naturally be closely monitored. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. J Clin Psychiatry 49:448–449. Br J Clin Pharmacol 45:176– 178. 1998 Parker AC. 2 mg/day. 1988 Brown CS. 2004). this decrease in the imipramine + desipramine blood level led to a loss of efficacy in treating this condition. Br J Clin Pharmacol 45:525–538. Epstein S. especially in children and adolescents. Drug Metab Dispos 32:348–358. Wells BG. 7-ethoxycoumarin. Cold JA. Eur J Clin Pharmacol 59:879–882. whose mass and metabolism are constantly in flux. This led to a decrease in the blood level of imipramine + desipramine (imipramine’s primary metabolite) (Brown et al. Krausz KW. Hamilton GA. Clin Pharmacokinet 31:198–214. References Arana GW. Neuvonen M.200 Drug–Drug Interaction Primer Ucar et al. 1990 Faucette SR. J Clin Psychopharmacol 10:359–362. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. Wang H. 1996 Ucar M. Luurila H. et al: Possible influence of carbamazepine on plasma imipramine concentrations in children with attention deficit hyperactivity disorder. and benztropine (Cogentin).

The blood level was probably somewhat higher than 4 ng/mL or benztropine would probably not have been a necessary adjunct in treating the parkinsonian symptoms that occurred without benztropine while the patient was taking 10 mg/day of haloperidol. The patient found this state of affairs quite upsetting and agreed to be hospitalized.C. 2001. Phenytoin is an inducer of multiple enzymes. The increase in the . Thus it appears that 3A4 is the P450 enzyme through which this interaction occurred. 1998. 2D6. However. When the phenytoin was added. Although there was no baseline haloperidol level for comparison. it would likely have been greater than 4 ng/mL at baseline. which was effective in preventing further seizures. Once his haloperidol dosage was increased to 40 mg/day. even though the dosage had not been changed (Linnoila et al. A trough haloperidol blood level drawn on admission was less than 2 ng/mL. Gibson et al. 2C19. This decrease in the haloperidol blood level allowed for a reemergence of active delusions and the patient’s accompanying clinical decompensation.7 µg/mL). specifically including 2C9. and phenytoin is an inducer of the glucuronidation 1A4 enzyme (Hachad et al. 2002). 3A4. 16. 300 mg/day (blood level. Haloperidol is metabolized by 3A4. May 2002). Chetty et al.Neurology Case Vignettes 201 ing phenytoin (Dilantin). 2002. the patient refused to leave his apartment except for grocery shopping and visiting his psychiatrist. Raucy 2003). Armstrong. producing a blood level of 7. 1A2. the patient developed the delusion that he was Keanu Reeves and that everyone and everything around him was a computergenerated false reality whose sole purpose was to trick him into revealing the security and access codes for America’s secret anthrax supply. and phase II glucuronidation (Desai et al. and uridine 5′-diphosphate glucuronosyltransferase 1A4 (Bottiger et al. he began to experience a decrease in the intensity of his paranoid and grandiose delusions (S. within 2 months of starting the phenytoin. Part of this decrease in the haloperidol blood level may also be attributable to the induction of phase II glucuronidation.2 ng/mL. Kudo and Ishizaki 1999). 1980). Although the specifics have not yet been well characterized. To protect himself. because that is considered the minimum effective blood level (although this threshold is far from reliable). haloperidol also relies on phase II glucuronidation for a significant portion of its metabolism. Discussion This is an example of an inducer added to a substrate. the amount of 3A4 that was available to metabolize the haloperidol increased. 1999. and this led to a lower haloperidol blood level. personal communication. Thus the increased production and metabolic efficiency of this 1A4 enzyme may also have contributed to this inferred decrease in the haloperidol blood level.

1. Drug Metab Dispos 31:533–539. Ragueneau-Majlessi I. Seymour MA: Phenytoin autoinduction. She even became tremulous and slightly confused. She visited a sleep specialist (neurologist). However. but she attributed these symptoms to withdrawal from the caffeine and regarded them as a sign of just how physiologically dependent she had become on caffeine. Jann MW: Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. Seabolt J. which had not reliably responded to trazodone (Desyrel). When a full week free of caffeine did not produce any improvements. 0. el-Sankary W. Viukari M. 300 mg/day. augmented with lithium. Am J Psychiatry 137:819–821. Toxicology 181–182:199–202. 1980 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. 1999 Linnoila M.202 Drug–Drug Interaction Primer haloperidol dosage to 40 mg/day appeared to compensate for phenytoin’s induction of haloperidol’s metabolism. Although she had expected some transient fatigue in the caffeine-tapering period. He advised the patient to gradually decrease her intake of caffeine in the hope that this would prove more helpful than aggressive sleep-inducing medications. CNS Drugs 15:469–494. 2002 Hachad H. 1999 Chetty M. Levy RH: New antiepileptic drugs: review on drug interactions. her malaise and significant sedation were well beyond anything she had anticipated. she suspected another cause for her difficulties. Stahle L: Lamotrigine drug interactions in a TDM material. 2001 Gibson GG. however.350 mg qhs (blood level. Within 2 weeks. 2002 Kudo S. Ther Drug Monit 21:171–174. Clin Pharmacokinet 37:435–456. 2003 DECAFFEINATION INTOXICATION A 29-year-old woman with recurrent major depression had been responding well to venlafaxine (Effexor). the patient had successfully weaned herself from all caffeinated beverages. 1998 Desai HD. References Bottiger Y.85 mEq/L). Vaisanen K. Svensson JO. low-dose mirtazapine (Remeron). Miller R. she had also been reporting chronic sleep difficulties. She contacted her psychiatrist and described the findings and recom- . Ishizaki T: Pharmacokinetics of haloperidol: an update. Ther Drug Monit 24:91–103. Ther Drug Monit 20:60–62. et al: Effect of anticonvulsants on plasma haloperidol and thioridazine levels. who took a full sleep hygiene and dietary inventory and discovered that the patient was a prolific consumer of coffee and caffeinated soda throughout the day. or various sedativehypnotic agents. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene.

1988 MIGRAINEUR A 30-year-old woman with a history of anxious depression was responding well to sertraline (Zoloft). as well as other xanthines like theophylline. Warner MD. When the caffeine was removed. References Finley PR. As stated in the case “More Than He Bargained For” in Chapter 2. She contacted her neurologist. the psychiatrist opted to allow the patient to remain at home. her blood level was 0. 75 mg po as needed for migraine headache.9 mEq/L at a dosage of only 900 mg/day of lithium. flushing. One week later. 1995 Jefferson JW: Lithium tremor and caffeine intake: two cases of drinking less and shaking more. lithium is primarily renally excreted. nausea. she had a migraine and took one of the sumatriptan tablets. including sodium and lithium (Finley et al.85 mEq/L to 0.9 mEq/L). Discussion This is an example of a state of mild lithium toxicity resulting from the discontinuation of caffeine.350 mg/day (Jefferson 1988). she experienced myoclonic jerking of her extremities. The neurologist prescribed sumatriptan (Imitrex). the rate of lithium excretion declined. 100 mg/day. Caffeine. which had grown more frequent and painful since she began her new job. After discussing options. Even with this decrease in dosage. who advised her to report to the emergency room immediately. Clin Pharmacokinet 29:172–191. she consulted with a neurologist for treatment of migraine headaches. leading to an increase in the lithium blood level and symptoms of mild lithium toxicity at the lithium dosage of 1.Neurology Case Vignettes 203 mendations of the sleep specialist. fever. the patient’s “decaffeinated” lithium level increased slightly (from 0. Peabody CA: Clinical relevance of drug interactions with lithium. but he instructed her to skip her next dose of lithium and then reduce her dosage to 900 mg qhs.85 mEq/L even in the face of caffeine’s excretion of lithium. which results in increased excretion of most solutes. acts as a diuretic by increasing the glomerular filtration rate and renal blood flow. She recov- . Within 2 hours. One week later. Two months after starting a new job. 1995). however.350 mg/day) was able to generate the lithium blood level of 0. The patient’s baseline lithium dosage (1. and tremor. J Clin Psychiatry 49:72–73. The psychiatrist compensated for this likely state of mild lithium toxicity by decreasing the lithium dosage by 33% (to a new dosage of 900 mg/day).

Lakartidningen 99:2054–2055. and possibly other postsynaptic serotonergic effects. however. titrated to a dosage of 150 mg/day. she developed trigeminal neuralgia and . Discussion This is an example of a central serotonin syndrome caused by the additive and possibly synergistic effects of sertraline and sumatriptan (GlaxoSmithKline 2001). and good communication and contingency planning in the event of a worst-case scenario should be undertaken prospectively with patients who are taking these medications concurrently. Personne M. her psychiatrist initiated a trial of lamotrigine (Lamictal). Sumatriptan is a potent and specific agonist of the serotonin receptor 5-HT1D. casual. However. 2002 MOTHER SUPERIOR A 75-year-old woman who served as the mother superior at a local convent had been diagnosed with bipolar II disorder. This effect seems to have combined with sumatriptan’s specific 5-HT1D agonism. et al: Serotonin syndrome: several cases of this often overlooked diagnosis. For most of her adult life. or unreflective manner. They were either poorly tolerated or ineffective. However. 2001 Hojer J. to produce a central serotonin syndrome (Hojer et al. Two years ago. which makes serotonin more systemically available. These combinations are certainly not absolutely contraindicated. GlaxoSmithKline. It is worth noting that this interaction between sertraline (or any of the selective serotonin reuptake inhibitors) and sumatriptan (or any of the “triptans”) is quite uncommon. NC. 2058–2060. Sertraline nonspecifically mobilizes more serotonin to bind with the whole array of postsynaptic serotonin receptors. to which she responded better than anyone had expected. it is frequent enough and serious enough that sumatriptan should not be added to these agents in a routine. Sertraline is a potent inhibitor of serotonin reuptake. Skagius AS. References GlaxoSmithKline: Imitrex (package insert). as if it was a matter of standard practice. including 5-HT1D. via serotonin reuptake inhibition. 2002) in this patient. her symptoms had been poorly responsive to the range of antidepressants and mood stabilizers. Research Triangle Park.204 Drug–Drug Interaction Primer ered fully after 48 hours of observation and treatment with lorazepam (Ativan) and antipyretic medication. but care should be exercised with sumatriptan dosing.

7. Lucas et al. Accordingly. 2002). 1996. Miners and Birkett 1998. yet several other studies from 1997 onward strongly suggested that there is no increase in carbamazepine-10. 1996. leading to a decrease in the blood level of lamotrigine. Lamotrigine is primarily metabolized through phase II glucuronidation. 1998. Eriksson and Boreus 1997. specifically including 1A2. Ucar et al.Neurology Case Vignettes 205 visited a neurologist for evaluation and treatment. She quickly contacted her psychiatrist and informed him of her current clinical state. her depressive symptoms had remitted. (She had tolerated carbamazepine in the past. Rambeck et al. . Discussion This is an example of an inducer added to a substrate. 1988. Within 3 weeks of achieving this new dosage. Hachad et al. which proved quite effective for her pain. 1999. 1997). Spina et al.5 µg/mL). Faucette et al. A prudent course would be to coadminister these agents as is clinically indicated but also to maintain an awareness of the possibility of such an interaction should symptoms of confusion and/or lethargy arise. she began to experience the familiar and dreaded sensation of evolving depression. and 3A4. which was therefore able to metabolize the lamotrigine more efficiently. Carbamazepine is an inducer of multiple P450 enzymes. There is some debate as to whether the addition of lamotrigine to carbamazepine increases the production of the neurotoxic carbamazepine10. He prescribed carbamazepine (Tegretol). but it had proven ineffective for her moodrelated symptoms. he titrated the lamotrigine dosage to double its previous amount (from 150 mg/day to 300 mg/day) and thus compensated for the effect of carbamazepine on the metabolism of lamotrigine. however. 1999). The psychiatrist was aware that the presence of carbamazepine leads to significant reductions in lamotrigine blood levels.11-epoxide metabolite. 1998. DeVane and Nemeroff 2002. even though the lamotrigine dosage had not been decreased (Bottiger et al. 1992). 1998. A 1992 study suggested that this was the case (Warner et al. It also induces UGT1A4 (Arana et al. titrated to a dosage of 600 mg/day (blood level. 2004).) One month after starting the carbamazepine. 2B6. Bottiger et al. 1999. 2C9. The psychiatrist promptly gave her a titration schedule for a new lamotrigine target dosage of 300 mg/day. specifically by the uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 enzyme (Hiller et al. This decrease in the lamotrigine blood level likely led to the patient’s impending depression. as well as the recent addition of carbamazepine to her regimen. The addition of carbamazepine led to the increased production of 1A4. Parker et al. Gidal et al. 2004.11-epoxide with the addition of lamotrigine (Besag et al.

J Clin Psychiatry 49:448– 449. et al: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. 1998 Bottiger Y. Ther Drug Monit 24:91–103. Br J Clin Pharmacol 45:176–178.206 Drug–Drug Interaction Primer References Arana GW. 1996 Ucar M. 1998 Miners JO. Nemeroff CB: 2002 guide to psychotropic drug interactions. Stahle L: Lamotrigine drug interactions in a TDM material. Bergstrom RF: A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism. Ther Drug Monit 19:499–501. Ther Drug Monit 21:171–174. et al: Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test. Prim Psychiatry 9:28–57. 1992 . Epilepsy Res 11:147–150. et al: Effect of lamotrigine on carbamazepine epoxide/ carbamazepine serum concentration ratios in adult patients with epilepsy. Pritchard P. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. Gilfillan DJ. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. et al: Carbamazepine toxicity with lamotrigine: pharmacokinetic or pharmacodynamic interaction? Epilepsia 39:183–187.11-epoxide. Eur J Clin Pharmacol 54:639–643. 1998 Parker AC. Nguyen N. 1996 Spina E. 1997 Hachad H. Strassburg CP. 2002 Eriksson AS. Wang H. Hamilton GA. 1988 Besag FM. et al: Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-10. Wolf P: Pharmacokinetic interactions of the new antiepileptic drugs. et al: Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Pool F. Clin Pharmacokinet 31:309–324. Clin Pharmacokinet 31:198–214.11-epoxide during addition of lamotrigine treatment in children. 1998 Rambeck B. Neuvonen M. Eur J Clin Pharmacol 59:879–882. 2004 Gidal BE. Drug Metab Dispos 32:348–358. Drug Metab Dispos 27:605–612. Epstein S. 1999 Lucas RA. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Svensson JO. Prevett M. Epilepsy Res 28:207–211. Patsalos PN. Molloy M. 2004 Warner T. 2002 Hiller A. Luurila H. Berry DJ. Shaw R. Boreus LO: No increase in carbamazepine-10. Preston T. 1997 Faucette SR. Birkett DJ: Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Ragueneau-Majlessi I. Pisani F. Specht U. 1999 DeVane CL. Br J Clin Pharmacol 45:525–538. Levy RH: New antiepileptic drugs: review on drug interactions. Rutecki P.

specifically by the uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 enzyme (Hiller et al. she reported recurring depressive symptoms to her psychiatrist. Discussion This is an example of an inducer added to a substrate.2 µg/mL). Miller R. Stahle L: Lamotrigine drug interactions in a TDM material. 300 mg/day (blood level. The psychiatrist was aware that the addition of phenytoin would lead to a significant reduction in the lamotrigine blood level. The addition of phenytoin led to the increased production of 1A4. during which she had been moderately euthymic and virtually seizure free. 2C19. Chetty et al. he titrated the lamotrigine dosage to double its previous amount (from 300 mg/day to 600 mg/day) and thus compensated for the effect of phenytoin on the metabolism of lamotrigine. One month later. References Bottiger Y. Seymour MA: Phenytoin autoinduction. Svensson JO. Phenytoin is an inducer of multiple enzymes. and UGT1A4 (Bottiger et al. Gibson et al. She immediately stopped having weekly seizures. 1999). Her neurologist could not pinpoint an obvious cause for this change in her seizure frequency. specifically including 2C9. leading to a decrease in the blood level of lamotrigine. 1999. 1998. Raucy 2003). to her lamotrigine.Neurology Case Vignettes 207 SEIZED BY SADNESS A 25-year-old woman with bipolar I disorder and a seizure disorder had been successfully maintained on lamotrigine (Lamictal) monotherapy (300 mg/day) for 18 months. 13. The psychiatrist instructed the patient to increase her lamotrigine dosage by 50 mg per week until she reached a dosage of 600 mg/day. who learned only at that time about the addition of the phenytoin to her regimen. 1999 Chetty M. 1998 . Ther Drug Monit 21:171–174. This decrease in the lamotrigine blood level likely led to her emerging depression. However. she experienced an increase in the frequency of her seizures from once every 6 months to once each week. Hachad et al. Lamotrigine is metabolized primarily through phase II glucuronidation. about 2 months ago. 2002. but he decided to add phenytoin. 1999. even though the lamotrigine dosage had not been decreased (Bottiger et al. 2002). Accordingly. Ther Drug Monit 20:60–62. 3A4. which was therefore able to more efficiently metabolize the lamotrigine. The patient complied. and her depressive symptoms abated.

as an anticoagulant agent. 1999 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Dispos 31:533–539. also shares this profile of inhibiting platelet aggregation. and he decided on his own to start taking ginkgo concentrated extract. After stopping the ginkgo. 40 mg bid. He contacted his neurologist. the patient found two large. Levy RH: New antiepileptic drugs: review on drug interactions. 2002 Hachad H. T oxicology 181–182:199–202. 2003 NATURAL DISASTER (IV) A 76-year-old man with a history of transient ischemic attacks was taking aspirin (Ecotrin).208 Drug–Drug Interaction Primer Gibson GG. 1997 . He read in a popular magazine about the cognition-enhancing effects of ginkgo (Ginkgo biloba). The antiplatelet effects of these two agents synergized to produce excessive anticoagulation. N Engl J Med 336:1108. painful bruises and several small petechiae on his arms. References Loew D: Value of Ginkgo biloba in treatment of Alzheimer dementia. Ther Drug Monit 24:91–103. resulting in excessive inhibition of platelet aggregation. 325 mg/day. He began to experience a subjective sense of word-finding difficulty and slowed thinking. the patient had no further hemorrhagic events (Rosenblatt and Mindel 1997). Wien Med Wochenschr 152:418–422. One week later. 2002 Hiller A. in addition to actual demonstrated efficacy in the treatment of Alzheimer’s dementia (Loew 2002). Mindel J: Spontaneous hyphema associated with ingestion of Ginkgo biloba extract (letter). Nguyen N. This type of synergy also occurs when warfarin (Coumadin) is combined with ginkgo (Lambrecht et al. Aspirin is used as a prophylactic agent to prevent ischemic vascular events by virtue of its ability to inhibit platelet aggregation. et al: Retigabine N-glucuronidation and its potential role in enterohepatic circulation. 2002 Rosenblatt M. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. Discussion This is an example of excessive pharmacodynamic synergy. Ginkgo. 2000). Cessation of the ginkgo reversed this effect. Ragueneau-Majlessi I. who advised discontinuing the ginkgo. el-Sankary W. There is a documented case of a 78-year-old woman who suffered a left parietal hemorrhagic cerebrovascular accident as a result of this interaction. Drug Metab Dispos 27:605–612. Strassburg CP. He feared that he was beginning to display symptoms of vascular dementia.

Drug Metab Dispos 29:1123–1129. 2005). 8. The carbamazepine did relieve the neuralgia pain. 6 months later the patient experienced a resurgence of depressive symptoms. Prudent clinicians are advised to beware of this potential complication when combining these agents. Hawke RL. Thus.2 µg/mL). this prompted the psychiatrist to confer with the neurologist. 2001 . but the available evidence strongly suggests that the addition of carbamazepine may undermine the antidepressant efficacy of bupropion. Carbamazepine is an inducer of multiple P450 enzymes. 2001). no study has examined the clinical effects of these ratios when they are generated by coadministration of bupropion with a P450 2B6 inducer. 1995). However.Neurology Case Vignettes 209 TRIGEMINAL TRIBULATIONS (I) A 55-year-old male with a history of recurrent major depression had been stably maintained for the past few years on bupropion (Wellbutrin XL). The neurologist added carbamazepine (Tegretol). 2000 Faucette SR. Lecluyse EL. 2004). this case is somewhat theoretical and conjectural in nature.400 mg/day. Carbamazepine has been shown to drastically reduce levels of bupropion. although levels of the primary active metabolite. eventually titrating to a total daily dosage of 2. hydroxybupropion. bupropion is roughly twice as potent a norepinephrine reuptake inhibitor as hydroxybupropion (Jefferson et al. which proved as effective as the carbamazepine for treating the trigeminal neuralgia. 300 mg every morning. He developed trigeminal neuralgia and was referred to a neurologist to address this condition. the neurologist opted to discontinue the carbamazepine and start gabapentin (Neurontin). Hawke RL. As a result. and at least one study has demonstrated that higher parent-to-metabolite ratios predict better response. Shord SS. 2000. titrated to a dosage of 400 mg bid (blood level. Drug Metab Dispos 28:1222–1230. et al: Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. rise almost as much (Ketter et al. et al: Evaluation of the contribution of cytochrome P450 3A4 to human liver microsomal bupropion hydroxylation. whereas lower parent-to-metabolite ratios predict poorer response (Golden et al. When he reported this depressive recurrence to his psychiatrist. the patient’s depression had again remitted. Within 6 more weeks. specifically including 2B6 (Faucette et al. References Faucette SR. However. Discussion This is an example of an inducer added to a substrate. Bupropion is a substrate of P450 2B6 (Faucette et al. 1988). However.

DeVane CL. et al: Carbamazepine but not valproate induces bupropion metabolism. 2000). he performed some research and then proceeded to increase her mirtazapine dosage to 60 mg/day. 2D6. This led to a referral to a neurologist. titrating to a dosage of 300 mg bid (blood level. titrating to 30 mg/day. and insomnia. 1996. Discussion This is an example of an inducer added to a substrate. References Arana GW. Within a month. Muir KT: Bupropion for major depressive disorder: pharmacokinetic and formulation considerations. 1998. Clin Ther 27:1685–1695. 2005 Ketter TA. Spina et al.210 Drug–Drug Interaction Primer Faucette SR. resulting in a decrease in the blood level of mirtazapine and loss of antidepressant efficacy. Wang H. and 3A4 (Stormer et al. Molloy M. One month later. The psychiatrist compensated for this effect by doubling the previous dose of mirtazapine. Parker et al. Schroeder DH. Drug Metab Dispos 32:348–358. Roughly 1 year later. she experienced a near-remission of her symptoms. 7. 2004). even though the dosage had not been decreased. 1988 . this led to a significant increase in the amount of 1A2 and 3A4 that were available to metabolize the mirtazapine. Epstein S. Pradko JF. Arch Gen Psychiatry 45:145–149. Timmer et al. 2004 Golden RN. She was referred to a psychiatrist. she had regained her prior level of antidepressant response with no ill effects. After 5 weeks. II: the role of metabolites in clinical outcome. et al: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. who opted to start the patient on carbamazepine (Tegretol). et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. Laizure SC. who started her on mirtazapine (Remeron). 1995 TRIGEMINAL TRIBULATIONS (II) In the context of multiple recent deaths of friends and family. Mirtazapine is a substrate of P450 1A2. Hamilton GA. including 1A2 and 3A4 (Arana et al. When carbamazepine was added to the mirtazapine. et al: Bupropion in depression. the addition of carbamazepine results in a 60% decrease in mirtazapine blood levels (Timmer et al. J Clin Psychiatry 49:448–449. Ucar et al. 2000). When she reported this to her psychiatrist. she developed trigeminal neuralgia. weight loss. Carbamazepine is an inducer of multiple P450 enzymes. One study indicates that on average. the patient experienced a partial recurrence of her prior depressive symptoms. 1988 Jefferson JW. 2000. J Clin Psychopharmacol 15:327–333. Jenkins JB. 1988. a 66-year-old woman had developed new-onset major depression with prominent anxiety.7 µg/mL). leading to a restoration of full antidepressant efficacy.

The neurologist recommended medications rather than surgery at this juncture. 2004). 2D6. he accused her of being in league with the French Secret Service and became threatening. An update. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine.3 µg/mL). Delbressine LP: Clinical pharmacokinetics of mirtazapine. Preston T. He had recently seen a performance of Les Miserables and was identifying with the character Jean Valjean. Neuvonen M. After communicating with his outpatient psychiatrist and neurologist. 1996 Stormer E. Aripiprazole is a substrate of P450 2D6 and 3A4 (Bristol-Myers Squibb 2005). Sitsen JM. 1998 Spina E. 1996.Neurology Case Vignettes 211 Parker AC. Ucar et al. Carbamazepine is an inducer of multiple P450 enzymes. 2004 24601 A 22-year-old male college student with bipolar I disorder was maintained on monotherapy with aripiprazole (Abilify). titrating to 800 mg/day (blood level. et al: Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test. Luurila H. 30 mg/day. Pisani F. and 3A4. carbamazepine. Drug Metab Dispos 28:1168–1175. 1988. Clin Pharmacokinet 38:461–474. largely due to his concerns about weight gain with any other medications. His seizures largely abated over the following weeks. the inpatient psychiatrist opted to increase the patient’s aripiprazole dosage to 60 mg/day. he was involuntarily admitted to a psychiatric facility and his medication regimen was reviewed. Spina et al. Br J Clin Pharmacol 45:176–178. 2000 Ucar M. and he was eventually able to be successfully discharged on this medication at this higher dosage. he also began to express increasingly grandiose and paranoid ideation. and lorazepam (Ativan). The patient continued to refuse any medications besides aripiprazole. Shader RI. Pritchard P. At this point. He began to experience periods of “blanking out” and repetitive motor behaviors. 2000 Timmer CJ. et al: Metabolism of the antidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. When . 8. specifically including 3A4 (Arana et al. and he was eventually referred to a neurologist. However. von Moltke LL. Eur J Clin Pharmacol 59:879–882. and he placed the patient on carbamazepine. A thorough workup led to the diagnosis of new-onset complex partial seizures due to a cavernous angioma. Discussion This is an example of an inducer added to a substrate. Clin Pharmacokinet 31:198–214. When he met with his psychiatrist.

titrated to 4 mg/day. although they . 2004 HOMELESS While trying to prevent his coat from being stolen. Several other seizures followed in the succeeding weeks.212 Drug–Drug Interaction Primer carbamazepine was added to the aripiprazole. An update. Once he was taken to the hospital. Princeton. although they did not remit entirely. He was started on risperidone (Risperdal). Epstein S. this led to a significant increase in the amount of 3A4 that was available to metabolize the aripiprazole. the surgical team discovered that he endorsed an array of paranoid delusions and auditory hallucinations. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. leading to the diagnosis of schizophrenia. leading to a restoration of full efficacy as a mood stabilizer. J Clin Psychiatry 49:448–449. 2005). who started the patient on phenytoin (Dilantin). He managed to locate a police officer. NJ. he experienced his first generalized seizure. 1996 Ucar M. Within 2 months of starting phenytoin. Eur J Clin Pharmacol 59:879–882. Further collateral history from the family confirmed that these symptoms were longstanding. a 33-year-old homeless man suffered a severe assault that included closed head injury. 16. resulting in a decrease in the blood level of aripiprazole and loss of efficacy as a mood stabilizer. presumably as a delayed sequela of his assault. The Abilify package insert cites a 70% decrease in aripiprazole blood levels when carbamazepine is added (Bristol-Myers Squibb 2005). even though the dosage had not been decreased (deLeon et al. who then called an ambulance.” and he heard them making noises outside his door. 2005 Spina E. 1988 Bristol-Myers Squibb: Abilify (package insert). titrated to 400 mg/day (blood level. Neuvonen M. One year later. Clin Pharmacokinet 31:198–214. the patient became concerned that the friends of the men who assaulted him were monitoring him to find an opportunity to “finish the job. Cozza KL: The dosing of atypical antipsychotics. and he was referred to a neurologist. Armstrong SC. Molloy M. Bristol-Myers Squibb. Luurila H. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report.4 µg/mL). Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine. The psychiatrist compensated for this effect by doubling the previous dosage of aripiprazole. Pisani F. 2005 deLeon J. His delusions and hallucinations significantly decreased. Psychosomatics 46:262–273. References Arana GW.

Raucy 2003). 18. 500 mg/day (blood level. Drug Metab Dispos 31:533–539. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. Within 3 weeks. Cozza KL: The dosing of atypical antipsychotics. The next time his phenytoin level was checked. It had been discovered over the years that he required a blood level in the higher part of the normal range (10–20 µg/mL) in order to remain relatively seizure free. Phenytoin is an inducer of multiple P450 enzymes. Nemeroff CB: An evaluation of risperidone drug interactions. Discussion This is an example of an inducer added to a substrate. even though the dosage had not been decreased (Bork et al. Psychosomatics 46:262–273. resulting in a decrease in the blood level of risperidone and loss of antipsychotic efficacy. his paranoia and hallucinations had again largely abated. When phenytoin was added to the regimen. 1999 deLeon J. generalized. de Leon J: A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A. 2001 Gibson GG. thus it has been suggested that one can compensate for this by doubling risperidone dosages after phenytoin has been added (deLeon et al. was added to his regimen to address his coronary artery disease.Neurology Case Vignettes 213 were never there when he looked outside. Wedlund PJ. he proceeded to raise the dosage to 700 mg/day to try to bring the . 2005). 2002. It is estimated that adding phenytoin to risperidone results in a roughly 50% decrease in blood levels. Rogers T. J Clin Psychopharmacol 21:408–416. she increased the patient’s risperidone to 8 mg/day.7 µg/mL) for a longstanding. J Clin Psychiatry 60:469–476. References Bork JA. Although his neurologist did not understand why his phenytoin level had declined. el-Sankary W. 2003 ILLUSORY INTERACTION A 67-year-old man had been chronically treated with phenytoin (Dilantin). When he reported these concerns to his psychiatrist. this led to a significant increase in the amount of 3A4 that was available to metabolize the risperidone.0 µg/mL. tonicclonic seizure disorder. 1999). Armstrong SC. Several months ago aspirin. specifically including 3A4 (Gibson et al. it had declined to 14. Risperidone is a substrate of 2D6 and 3A4 (DeVane and Nemeroff 2001). Toxicology 181–182:199–202. 2002 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. 325 mg/day. 2005 DeVane CL.

However.214 Drug–Drug Interaction Primer level back to the higher part of the standard therapeutic range. It was not the drug– .1 µg/mL. this free fraction. However. do not alter free concentrations. Discussion This is an example of plasma protein binding displacement without accompanying metabolic inhibition. In fact. nystagmus. then there can be no situation in which they become clinically significant. Aspirin and phenytoin are both highly plasma protein–bound drugs (Kodama et al.” can pose real clinical problems for patients. It would be tempting to conclude that because pure displacement drug– drug interactions. However. this maneuver actually produced an iatrogenic case of mild phenytoin toxicity. the decrease in the total phenytoin level led the clinician to (inaccurately) believe that he needed to increase the phenytoin dosage in order to preserve anti-seizure efficacy. One study demonstrated that this combination produced no changes in free phenytoin concentrations but that total phenytoin concentrations decreased by a mean of roughly 27% (Miners 1989. 2000. which was 2. the neurologist obtained a free phenytoin level. when they interface with “standard practice. The net result of these processes is that once equilibrium is achieved. and it is therefore completely safe to simply follow total concentrations.5 µg/mL (normal range. and the total concentration actually decreases.2 µg/mL and free phenytoin level of 1. the free fraction of phenytoin remains elevated. the level had risen to 19. pure displacement interactions. and sedation. there is increased clearance of the free fraction that compensates for the increased ratio of free-to-bound drug that is produced by the reciprocal displacement. The patient’s symptoms had also abated by that time. After consulting with a colleague. Lim et al. Thus. This produces elevations in the free fraction of both drugs. 1–2 µg/mL). The patient had also demonstrated these symptoms many years ago. in addition to being the pharmacologically active fraction of drug. the free concentration is unchanged. and analogous situations such as hypoalbuminemia. because aspirin does not in any way inhibit the metabolism of phenytoin. Paxton 1980). is also the fraction that is available for clearance. but the patient had developed a new tremor. Within 1 week. He then decreased the patient’s phenytoin dosage back to 500 mg/day and 1 week later obtained a total phenytoin level of 14.9 µg/mL. The addition of aspirin to phenytoin produced no change in the free phenytoin concentration and thus no phenytoin toxicity. when previous attempts at dosage titration had produced blood levels in the 22–26 µg/mL range. With the addition of aspirin to phenytoin. as this case illustrates. 1986). there is mutual displacement from plasma protein binding sites between aspirin and phenytoin.

Thus. Clin Pharmacokinet 17:327–344. Wynne KN. 2000 Lim CF. 1986 Miners JO: Drug interactions involving aspirin (acetylsalicylic acid) and salicylic acid. 1989 Paxton JW: Effects of aspirin on salivary and serum phenytoin kinetics in healthy subjects. there can be some utility and a coherent rationale for following free concentrations of highly bound drugs like phenytoin and valproate. Barned JM. et al: In vivo binding characteristics of phenytoin to serum proteins in monotherapy for adults with epilepsy. Rather. J Pharm Pharmacol 38:795–800. References Kodama H. Shinozawa S. et al: Non-isotopic spectrophotometric determination of the unbound fraction of drugs in serum. even in the absence of metabolic inhibition and resulting changes in free concentrations.Neurology Case Vignettes 215 drug interaction that produced the toxicity. 1980 . Am J Ther 7:359–363. Clin Pharmacol Ther 27:170–178. Kodama Y. the interpretation that followed from using total versus free phenytoin levels led the clinician astray.

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May 2002). Discussion This is an example of an inhibitor added to a substrate. with no loss of antidepressant efficacy (S. for which she renewed her use of fluoxetine (Prozac).Chapter 5 SURGERY/ANESTHESIA CASE VIGNETTES SAD AND SORE A 35-year-old woman underwent a splenectomy after a car accident in which she experienced severe blunt abdominal trauma and multiple other orthopedic injuries. which provided adequate analgesia. she regained the analgesic response from the Vicodin. Armstrong. 20 mg/day. The accident led to a recurrence of her major depressive disorder. Hydrocodone is actually a pro-drug. and 4 days later started her on citalopram (Celexa). 1993). which catalyzes its transformation into hydromorphone (Dilaudid) (Otton et al. Hydrocodone is a substrate of 2D6. 20 mg/day. but she also experienced a corresponding waning of analgesic effect from her usual dose of Vicodin. Over the next 3 weeks. Fluoxetine is a strong 2D6 inhibitor (see Stevens and 217 . Her psychiatrist discontinued her fluoxetine. personal communication.C. she began to experience a remission of her depressive symptoms. Her surgeon prescribed Vicodin (acetaminophen plus hydrocodone) for postoperative pain. Over the next 3 weeks.

which is only a mild to moderate inhibitor of 2D6 (Brosen and Naranjo 2001. Despite her prior directive. muscle twitching. Thus. the addition of the fluoxetine impaired the ability of 2D6 to transform hydrocodone into hydromorphone. led to a significant decrease in the degree of 2D6 inhibition. Clin Pharmacol Ther 54:463–472. MO. with good success. whereupon she was transferred back to the surgical floor. This allowed for sufficient renewed conversion of hydrocodone to hydromorphone to produce a return of analgesia. she fell and suffered a left humeral fracture. 1993 “I GET DELIRIOUS” A 45-year-old woman with recurrent major depressive disorder and a family history positive for opioid dependence was being maintained on paroxetine (Paxil).218 Drug–Drug Interaction Primer Wrighton 1993). The surgeon suspected an infection and began an appropriate workup. even after the postictal period had passed. 1993 Stevens JC. she explained to her surgeon that she did not want to receive any conventional narcotics because she was afraid of becoming “hooked” like her parents. Schadel M. and after 4 days she experienced increasing flushing. The switch to citalopram. even as it provided antidepressant efficacy. 20 mg/day. Eur Neuropsychopharmacol 11:275–283. St. Forest Pharmaceuticals. and confusion as to time and place. Louis. fevers. 2001 Forest Pharmaceuticals: Celexa (package insert). Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. and her tramadol and paroxetine were both discontinued. While skiing with her family. et al: CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. sedation. and this prompted the surgeon to consult . she was placed on parenteral morphine. She was maintained on her paroxetine as well. Her blood culture results were negative. Naranjo CA: Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. Once hospitalized. diarrhea. 75 mg po every 4 hours as needed for pain. While awaiting blood culture results. She was transferred to the intensive care unit in view of her persistent delirium and vital sign instability. Forest Pharmaceuticals 2004). the patient experienced a grand mal seizure. 2004 Otton SV. Cheung SW. with no loss of antidepressant efficacy in this patient. J Pharmacol Exp Ther 266:964–971. not to exceed 400 mg/day. She reported only partial relief from her pain. Her delirium and associated symptoms gradually resolved over the next few days. References Brosen K. He opted to order tramadol (Ultram).

Giambanco V: Serotonin syndrome following the administration of tramadol with paroxetine. when the substrate is a pro-drug. J Clin Psychopharmacol 15:125–131. Brosen K. and paroxetine was able to be restarted because it would not impair the analgesic efficacy of hydromorphone. the presence of the paroxetine impaired 2D6’s ability to efficiently metabolize the transformation of tramadol to M1. usually result in substrate toxicity states.Surgery/Anesthesia Case Vignettes 219 with the hospital pharmacist. the substrate–inhibitor interaction may lead to a lack of efficacy when the pro-drug is not transformed into the desired active metabolite. 1998) that culminated in a seizure. After this consultation. Tramadol is a substrate of 2D6 (which metabolizes tramadol to a more analgesic compound called M1) (Sindrup et al. The discontinuation of the inciting agents led to recovery. 1995). Clin Pharmacol Ther 60:636–644. 1996). 1996 Sindrup SH. NJ. but she was given hydromorphone (Dilaudid) instead of tramadol. Court MH. Buchalter EN. 1998 Ortho-McNeil Pharmaceutical: Ultram (package insert). Int J Geriatr Psychiatry 13:343–345. However. 1995 . Discussion This is an example of a substrate added to an inhibitor. When tramadol was added in standard doses for the treatment of acute pain. resulting in a central serotonin syndrome (Lantz et al. and paroxetine is a strong competitive inhibitor of 2D6 (von Moltke et al. Madsen C. OrthoMcNeil Pharmaceutical. Clin Pharmacol Ther 66:636–641. 1999 von Moltke LL. Raritan. Arendt-Nielsen L. She was eventually transitioned to nonsteroidal analgesics without further difficulties. when problematic. Greenblatt DJ. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. The other contributor to this case was a pharmacodynamic synergy between tramadol’s significant serotonergic blockade (and propensity to lower the seizure threshold) (Ortho-McNeil Pharmaceutical 2000) and that of paroxetine. 2000 Poulsen L. This interaction is somewhat counterintuitive in that substrate–inhibitor interactions. 1999). et al: The hypoalgesic effect of tramadol in relation to CYP2D6. Brosen K. et al: The effect of tramadol in painful polyneuropathy in relation to serum drug and metabolite levels. This accounted for the patient’s report of suboptimal analgesia from an adequate dose of tramadol (Poulsen et al. the patient was restarted on her paroxetine. References Lantz MS.

becoming forgetful and losing track of the time. References Kronbach T. even though the cyclosporine dosage had not been changed. 1988 . Discussion This is an example of an inhibitor added to a substrate. has been combined with cyclosporine (Vella and Sayegh 1998). experienced a seizure. insomnia. As a result of her cyclosporine toxicity. the patient became acutely confused and lethargic. the patient strongly desired to start taking an antidepressant. the ability of 3A4 to efficiently metabolize the cyclosporine was impaired. She eventually had a tonic-clonic seizure. She encountered no signs of organ rejection. She was normally vigilant about her health status. When the nefazodone was added to the regimen. which led the psychiatrist to select nefazodone (Serzone) as an appropriate antidepressant choice. This interaction has also occurred when fluvoxamine (Luvox). he titrated the nefazodone to a dosage of 400 mg/day. Over the course of 4 weeks. day. Sokal. Clin Pharmacol Ther 43:630–635. and date. and she tolerated this medication without difficulty. and nefazodone is a strong competitive inhibitor of 3A4 (von Moltke et al. and poor energy. but in her impaired mental state she did not report her worsening oliguria to her nephrologist. This led to an increase in the blood level of cyclosporine to the toxic range. Just as she reached this dosage. June 2002). The patient listed intact sexual functioning as an absolute priority and insomnia as her most troublesome symptom. poor concentration. a moderately strong 3A4 inhibitor. Fischer V. her curtailment of her previously active lifestyle and body image issues led to increasing dysphoria. leading to immediate hospitalization. personal communication. 1996). Although a consulting psychiatrist recognized both psychological and medical contributions to her depressive symptoms. Meyer UA: Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporinemetabolizing enzyme explains interactions of cyclosporine with other drugs. Cyclosporine is a 3A4 substrate (Kronbach et al. She was started on cyclosporine (Sandimmune).220 Drug–Drug Interaction Primer RENAL RECKLESSNESS A 37-year-old woman with no psychiatric history successfully received a renal transplant after a severe episode of rapidly progressive glomerulonephritis that was not recognized or treated in time. 1988). However. and developed acute renal failure. at which time she was found to be in acute renal failure (J. she began to grow increasingly lethargic and confused.

the morphine was completely effective and produced none of the previous side effects. Postoperatively. The meperidine was not providing effective analgesia. The patient’s visiting friends reported to the surgeon that he seemed more despondent and irritable than they would have expected.” then the rate of renal elimination of normeperidine is generally sufficient to clear this compound and prevent toxic accumulations. The next day. and ritonavir is a 3A4 inducer when administered chronically (Greenblatt et al. 2000. Discussion This is an example of a substrate added to an inducer. Greenblatt DJ. was struck by a car while he was bicycling on the road. and he was given morphine (MSIR) for his pain. who was taking ritonavir (Norvir) as one of his chronic medications. 25 mg intramuscularly every 4 hours as needed for postoperative pain. When the amount of metabolically available 3A4 is “normal. he was transferred to the orthopedic floor and was given meperidine (Demerol). et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. which is a renally excreted toxic meperidine metabolite with a much longer halflife (15–20 hours) than that of the parent compound (3–4 hours) (Wong 2002). even under these circumstances. Meperidine is at least a partial 3A4 substrate. where he had an open reduction of his left fibula fracture. After the patient recovered. Harmatz JS. HIV-positive man. 1998). 3A4 catalyzes the specific transformation of meperidine into normeperidine (Piscitelli et al. However. J Pharmacol Exp Ther 276:370–379. so long as meperidine dosing remains moderate and the treatment course is relatively brief (several days). 2000). so in 2 days the dosage was increased to 50 mg. Ritonavir is also a “pan-inhibitor” at all major P450 enzymes except for 1A2 and 2E1 (von Moltke et al. 1996 INDUCTION TOXICITY A 37-year-old. when ritonavir is chronically administered. this dosage provided only modest pain relief. the induction of 3A4 appears to overtake its inhibition. The patient was also noted to have developed a slight tremor. Three days later.Surgery/Anesthesia Case Vignettes 221 Vella JP. 1998 von Moltke LL. 2000). Sayegh MH: Interactions between cyclosporine and newer antidepressant medications. Piscitelli et al. the patient had a grand mal seizure. the meperidine was immediately discontinued. The resulting greater amount of available 3A4 leads to an increased rate of metabolic transforma- . He was admitted to the nearest hospital and taken to the operating room. Am J Kidney Dis 31:320–323.

2000 von Moltke LL.222 Drug–Drug Interaction Primer tion of meperidine into the normeperidine metabolite. Pharmacotherapy 20:549–553. titrating to a dosage of 150 mg qhs. Bertz RJ. [2000]). so the surgeon added cyclobenzaprine (Flexeril). 5 mg intramuscularly. Her previous depressive episodes had responded to amitriptyline (Elavil). and she experienced a recurrence of her depression as a consequence of her current disability. et al: The effect of ritonavir on the pharmacokinetics of meperidine and normeperidine. her surgeon ordered two successive doses of haloperidol (Haldol). according to Piscitelli et al. and a seizure.com/WOW/op024. She was hospitalized for a sustained period. Over the next week. in order to help calm her. leading to decreased blood levels of meperidine and increased blood levels of normeperidine (normeperidine’s area under the curve is increased by 47%.elsevierhealth. irritability. complaining about muscle stiffness and cramping. the surgeon started the patient on amitriptyline. 10 mg tid. although she had not taken this medication for more than 8 years. Greenblatt DJ.us. March 15. Accessed July 29. Grassi JM. with alternating periods of somnolence and increasingly severe agitation and irritability. Clin Pharmacol Ther 67:335–341. fell from a ladder while mending a shingle on her house and fractured her hip. tremor. At this point. roughly 3 hours apart. 200 mg/day. soon thereafter she experienced a cardiac arrest and expired despite efforts at resuscitation (R. while the increased normeperidine led to emerging dysphoria. After conferring with her previous psychiatrist. 2000 Piscitelli SC. et al: Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. in full remission. Available online at http://www3. Unfortunately. She was. J Clin Pharmacol 38:106–111. She was also receiving hydromorphone to treat her postsurgical pain. In this case. August 2002). Harmatz JS. Kress DR. . Love. von Moltke LL. 2002 STRUCTURAL SIMILARITIES AND CARDIAC CALAMITIES A 55-year-old woman with a history of major depressive disorder. 2002. however. the decreased meperidine led to less effective analgesia. personal communication. and this was providing adequate analgesia. She eventually became frankly combative and required restraints. 1998 Wong: Wong on Web Paper: Notes on Meperidine. References Greenblatt DJ. et al: Alprazolam-ritonavir interaction: implications for product labeling. the patient became increasingly confused.html.

With the addition of the haloperidol to the combination of amitriptyline and cyclobenzaprine. resulting in blood level elevations of all three agents. Amitriptyline. likely augmented their shared effects on cardiac conduction to produce this fatal outcome. CNS Drugs 15:469–494. Parra F: Psychotropic drugs and the ECG: focus on the QTc interval. and therefore the pharmacokinetic component of this drug interaction remains more conjectural than factual. 2002 Venkatakrishnan K.Surgery/Anesthesia Case Vignettes 223 Discussion This is an example of multiple inhibitor-added-to-substrate and substrate-added-to-inhibitor combinations. Drug Metab Dispos 24:786–791. Liu L. and haloperidol are all partially metabolized at 1A2 (Desai et al. no blood levels were drawn to verify that such an interaction was taking place. Jerry J. and it is probably the more important contributor to this adverse event. their likely mutual inhibition of one another’s metabolism. 1998. 1998 Wang RW. the net effect being some degree of elevation of the blood levels of all three agents. 2002). When these three agents were coadministered. Greenblatt DJ. Seabolt J. Expert Opin Pharmacother 3:479–498. Thus. (Although the haloperidol had only just been introduced. 2001. Cheng H: Identification of human liver cytochrome P450 isoforms involved in the in vitro metabolism of cyclobenzaprine.) Unfortunately. References Desai HD. 2001 Goodnick PJ. Venkatakrishnan et al. Haloperidol also has a recognized ability to prolong the QTc interval (Goodnick et al. et al: Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4. and thus it shares their quinidine-like effects on cardiac conduction. Jann MW: Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. synergizing with additive pharmacodynamic effects on cardiac conduction. this became a three-way reciprocal interaction. when the cyclobenzaprine was added to the amitriptyline. its intramuscular administration may well have enabled it to meaningfully participate in this three-way interaction. Wang et al. 1996). 1996 . The pharmacodynamic synergy between these agents is more straightforward. von Moltke LL. J Clin Pharmacol 38:112–121. each agent likely acted as both a competitive inhibitor slowing the metabolism of the other agent at 1A2 and a substrate whose metabolism at 1A2 was being impaired by the introduction of the other agent acting as a competitive inhibitor. Cyclobenzaprine is very closely related in structure to the tricyclic antidepressants. cyclobenzaprine.

The metabolism of droperidol is not well understood. the administration of droperidol under these circumstances almost certainly led to additional prolongation of the QTc interval. the presence of fluoxetine significantly impaired the ability of 3A4 (and possibly 2D6. 2C9. 1999. Three days later. and cyclobenzaprine (Flexeril). The patient reported that she had become nauseated the last time she was given a general anesthetic. and/or 2D6 for some of its metabolism. her QTc interval had decreased to 436 msec (Michalets et al. so she received preoperative droperidol (Inapsine). 3A4. 2C19. Her preoperative electrocardiogram revealed a QTc interval of 495 msec. 2002). and glucuronidation. 2C9. Fluoxetine (in concert with its active metabolite. Thus. structurally analogous to haloperidol (Haldol). beyond the inhibition of cyclobenzaprine’s metabolism at 3A4. leading to a greater blood level of cyclobenzaprine than would have existed at this dosage had the fluoxetine not been present. Her regular medications included fluoxetine (Prozac). Droperidol is a butyrophenone neuroleptic. and 2C19 (Greenblatt et al. Stevens and Wrighton 1993). it was discovered that her preoperative QTc . although its tricyclic structure suggests that it may also rely on 2C9.224 Drug–Drug Interaction Primer ANTIEMETIC ARRHYTHMIA A 61-year-old woman with recurrent major depression was admitted to a surgical service for an orthopedic procedure. Cyclobenzaprine is a substrate of both 1A2 and 3A4 (Wang et al. During the surgical procedure. which led to her cardiac arrhythmias. 1A2. the patient developed a torsades de pointes arrhythmia that progressed into ventricular fibrillation. When her fluoxetine and cyclobenzaprine were discontinued. 20 mg/day. However. these other pharmacokinetic considerations are conjectural. fluoxetine would have impaired the ability of 2D6 and 3A4 to metabolize the droperidol. and 2C19 as well) to contribute to the metabolism of cyclobenzaprine. norfluoxetine) is a strong 2D6 inhibitor and a moderate inhibitor of 3A4. but its similarity to haloperidol suggests that it may be metabolized by 2D6. If that is the case. 10 mg tid. 1998). leading to a greater-than-expected blood level of droperidol following the administration of the intravenous droperidol. She was successfully restored to normal sinus rhythm. Discussion This is an example of multiple substrate–inhibitor interactions synergizing with pharmacodynamic interactions between agents. Cyclobenzaprine (because of its close structural relationship to the tricyclic antidepressants) and droperidol both have the ability to prolong the QTc interval (Goodnick et al. and her fluoxetine and cyclobenzaprine were discontinued for the time being. 1996). 5 mg intravenously. Given that this patient had a quite long preoperative QTc interval.

Drug Metab Dispos 24:786–791. Her surgical intern ordered meperidine (Demerol). severe serotonin syndrome was caused by the interaction of phenelzine (a monoamine oxidase inhibitor) and meperidine. In this case. et al: Human cytochromes and some newer antidepressants: kinetics. Discussion This is an example of a “substrate” added to an inhibitor. was admitted to the surgical floor of a hospital for cholecystitis with severe. colicky abdominal pain. Because this . 1998 Stevens JC. Jerry J. The pharmacokinetic interactions likely maximized the ability of these agents to exert their pharmacodynamic influence on this patient’s cardiac conduction. Harmatz JS. because he had “learned” that meperidine was less likely than morphine to contract the sphincter of Oddi and thus exacerbate her cholestatic pain. Ann Pharmacother 32:761–765. whose metabolism was probably being slowed and whose blood level was probably being increased by fluoxetine. Cheng H: Identification of human liver cytochrome P450 isoforms involved in the in vitro metabolism of cyclobenzaprine. metabolism. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. 60 mg/day. Smith LK. 1996 CHOLESTATIC CATASTROPHE A 45-year-old woman whose atypical major depression was being well managed with phenelzine (Nardil). a narcotic analgesic that acts as a “serotomimetic agent” (Bodner et al. 1993 Wang RW. Despite all supportive attempts. the patient expired over the next 2 hours. she became acutely confused and agitated and developed a fever of 105. von Moltke LL. leading to greater QTc prolongation than would likely have occurred had the fluoxetine not been present. Expert Opin Pharmacother 3:479–498. Within 5 hours of receiving her first (and only) injection of meperidine. Van Tassel ED: Torsade de pointes resulting from the addition of droperidol to an existing cytochrome P450 drug interaction.9°F. 1995). Liu L. J Pharmacol Exp Ther 266:964–971. J Clin Psychopharmacol 19(suppl):23S–35S. 2002 Greenblatt DJ. This was likely due to the influence of cyclobenzaprine.Surgery/Anesthesia Case Vignettes 225 interval (495 msec) was significantly higher than her true baseline QTc interval (436 msec). 50 mg intramuscularly every 4 hours as needed for pain. and drug interactions. 1999 Michalets EL. Parra F: Psychotropic drugs and the ECG: focus on the QTc interval. References Goodnick PJ.

200 mg/day and added risperidone (Risperdal). Zion.250 mg/day (blood level.226 Drug–Drug Interaction Primer property of meperidine led to a rapid increase in synaptically available serotonin. et al: Serotonin syndrome. with a blood level of 0. This case mirrors the famous Libby Zion case. References Asch DA. The patient’s new lithium level was 0. . culminating in an acute central serotonin syndrome (Sporer 1995). the patient began to experience the emergence of manic symptoms. Four weeks after the indomethacin had been discontinued. Although he did not understand why the lithium level had declined. Neurology 45:219– 223. Drug Saf 13:94–104. in which Ms. and his divalproex was tapered and discontinued. the psychiatrist and patient both felt more comfortable transitioning from divalproex to lithium. pathophysiology and management. Three months later. Parker RM: The Libby Zion Case: one step forward or two steps backward? N Engl J Med 318:771–775.9 mEq/L. the patient’s tendinitis had resolved and his orthopedist felt that he should taper and discontinue the patient’s indomethacin. received meperidine in an emergency room for shaking chills. 1. 50 mg tid. His psychiatrist had a lithium level checked immediately and to his surprise found that it was only 0. 81 µg/mL). Although this need not have necessitated the discontinuation of divalproex. for persistent tendinitis. After 1 month on this regimen.9 mEq/L. titrated rapidly to a dosage of 4 mg/day. and because phenelzine inhibits the breakdown of all monoamines (including serotonin). 1988 Bodner RA. The patient eventually had his dosage of lithium titrated to 750 mg/day.6°F and died within 6 hours of her arrival in that hospital (Asch and Parker 1988). although the patient reported compliance with the lithium. and euthymia was restored. the combination of these two agents led to an acute and severe accumulation of serotonin. 1995 Sporer KA: The serotonin syndrome: implicated drugs. the patient’s liver function tests (γ-glutamyltransferase and alanine transaminase) rose to more than double their baseline values. he nonetheless increased the lithium dosage to 1. when he also began taking chronic indomethacin (Indocin). He rapidly responded to these interventions. Lewis L. who was regularly taking phenelzine. 1995 ORTHOPEDIC RECOVERY AND MANIC RECURRENCE A 27-year-old squash player with bipolar I disorder was being treated with divalproex sodium (Depakote).4 mEq/L. She developed a fever of 107. Lynch T.

References Finley PR. so close observation and frequent lithium levels are warranted. Therefore. 1997). the lithium blood level of 0.9 mEq/L. with the exception of aspirin and sulindac (Clinoril). and therefore a variety of medications that alter renal function can alter the rate of lithium excretion. Danion JM. and the addition of risperidone also helped to restabilize the patient. will often elevate lithium blood levels (Finley et al. 1997 Ragheb M: The clinical significance of lithium–nonsteroidal anti-inflammatory drug interactions. Ragheb 1990). As mentioned in “The Tremulous Triathlete” case in Chapter 2. The change in lithium blood level can be quite variable and difficult to predict. 1995. leading to a decrease in the lithium level to 0.Surgery/Anesthesia Case Vignettes 227 Discussion This is an example of reversal of inhibition. thus interfering with the excretion of lithium (Imbs et al. All nonsteroidal antiinflammatory drugs (NSAIDs.200 mg/day. Clin Pharmacokinet 29:172–191. Warner MD. was higher than it would have been had the indomethacin not been present. The proposed mechanism for this interaction is that NSAIDs inhibit prostaglandin synthesis in the kidney.4 mEq/L and a subsequent vulnerability to a manic switch. Therefore. including indomethacin). the patient’s kidneys were able to more efficiently excrete the lithium. et al: Mechanisms of drug interactions with renal elimination of lithium (in French). J Clin Psychopharmacol 10:350–354. at a dosage of 750 mg/day. 1995 Imbs JL. with the discontinuation of the indomethacin. The indomethacin was already present when the titration to a therapeutic dose and blood level of lithium occurred. Barthelmebs M. lithium is entirely renally excreted. The psychiatrist eventually compensated for this effect by increasing the lithium dosage to 1. 1990 . Peabody CA: Clinical relevance of drug interactions with lithium. Bull Acad Natl Med 181:685–697.

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and it did not respond to topical antifungal remedies (such as clotrimazole [Lotrimin] cream). the patient was additionally experiencing marked muscle twitching. who prescribed oral terbinafine (Lamisil). ONCOLOGY. titrating to a dosage of 100 mg/day. The imipramine was discontinued and the patient visited a local emergency room for observation. At that point. but he was released the same day because his electrocardiogram revealed only mild sinus tachycardia. His terbinafine was continued throughout. sleep. 250 mg/day. which generated an imip229 . the patient experienced worsening dysphoria and impaired concentration. generating imipramine + desipramine blood levels that ranged from 175 to 225 ng/mL. Within 1 week.Chapter 6 GYNECOLOGY. After learning that his patient had been prescribed and was taking terbinafine. Suspecting that these apparent neurovegetative changes represented one of the patient’s occasional and sporadic illness exacerbations. and appetite. He developed a painful and persistent case of onychomycosis under the nail of his left big toe. He consulted a dermatologist. One week later. AND DERMATOLOGY CASE VIGNETTES FUNGAL FRUSTRATION A 55-year-old man with a history of chronic major depressive disorder was being reasonably well managed with imipramine (Tofranil). the psychiatrist eventually had the patient restart imipramine. his psychiatrist increased the dosage of imipramine from 200 mg/day to 225 mg/day. 200 mg/day. It became so severe that it began to affect his gait. his imipramine + desipramine blood level was drawn and was found to be 575 ng/mL. and dizziness so severe that he fell just after rising from a sitting position. dry mouth.

Sai Y. and imipramine metabolism. Discussion This is an example of an inhibitor added to a substrate. Drug Metab Dispos 27:102–109. et al: Polymorphic 2-hydroxylation of desipramine: a population and family study. Desipramine is imipramine’s primary metabolite via demethylation by 2C19 and 3A4. the terbinafine was discontinued. 2D6. 1999 UNINTENDED FERTILITY A 20-year-old college student was using an oral contraceptive containing ethinylestradiol as her means of preventing pregnancy.230 Drug–Drug Interaction Primer ramine + desipramine blood level of 230 ng/mL. Drug Metab Dispos 27:770–775. et al: Potent inhibition of cytochrome P-450 2D6–mediated dextromethorphan O-demethylation by terbinafine. as well as to other side effects (dysphoria. Pearson VE: Imipramine toxicity and terbinafine. 3A4. even though the dosage had been increased from 200 mg/day to only 225 mg/day. decreased sleep. Yang et al. She had a boyfriend with whom she had engaged in intercourse approximately twice a week for the past 10 months. Introducing terbinafine into the patient’s regimen prevented 2D6 from effectively metabolizing both imipramine and desipramine. dry mouth. References Abdel-Rahman SM. Marcucci K. et al: Eight inhibitory monoclonal antibodies define the role of individual P450s in human liver microsomal diazepam. Imipramine is a tertiary-amine tricyclic antidepressant (TCA) whose metabolism depends most on the intact functioning of 2C19. Terbinafine is a strong 2D6 inhibitor (Abdel-Rahman et al. 1999 Dahl ML. whereupon the imipramine was again retitrated to 200 mg/day and his blood level remained basically constant (between 200 and 250 ng/mL) (Teitelbaum and Pearson 2001). and dizziness (which led to a fall). 1993 Teitelbaum ML. 7-ethoxycoumarin. Eur J Clin Pharmacol 44:445–450. Alm C. This TCA toxicity state led to the patient’s muscle twitching. 2001 Yang TJ. This led to a roughly threefold increase in the blood level of imipramine + desipramine. The oral contraceptive was their only method of birth . and impaired concentration) that mimicked an exacerbation of his major depressive disorder. After the patient’s onychomycosis resolved. 1999). 1993. 1999). Iselius L. and 1A2. poor appetite. Boge T. Krausz KW. 2D6 catalyzes hydroxylation of both imipramine and desipramine (Dahl et al. Am J Psychiatry 158:2086.

Three months later. John’s wort (Hypericum perforatum) at the local drugstore and began taking it per the attached instructions. By day 5 of the first week of itraconazole therapy. followed by a 3-week delay. 2003). During a period of increased stress and dysphoria. nausea. Huang SM. making it difficult for him to do his job. thick nails pierced through his gloves and into the base of the nail bed of his right index finger. The dermatologist prescribed itraconazole (Sporanox). with a subsequent loss of efficacy as a reliable method of birth control. and tremor.R. John’s wort. Even though he spent a lot of time sleeping. 2003 Moore LB. and swollen. Anderson GD. Jones SA. Kantor E. 1990 Hall SD. In the face of regular sexual activity. he picked up a plastic bag and two sharp. he was so highly motivated to treat this infection that he nonetheless complied with . more 3A4 was produced and therefore available to metabolize the ethinylestradiol. Life Sci 47:1981– 1988. she purchased some St. 2000 OCCUPATIONAL HAZARD A 34-year-old sanitation worker with generalized anxiety disorder was responding well to buspirone (BuSpar). Oesterheld. Roby et al. 2000. This led to lower blood levels of ethinylestradiol (Hall et al. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. the patient had experienced marked sedation. red. 2000 Roby CA. Oncology. et al: St. who diagnosed a fungal infection (onychomycosis). this area became extremely tender. Proc Natl Acad Sci USA 97:7500–7502. Discussion This is an example of an inducer added to a substrate. References Guengerich FP: Metabolism of 17 α-ethynylestradiol in humans. Ethinylestradiol is a 3A4 substrate (Guengerich 1990). then a repetition of the 200 mg bid for another week. et al: The interaction between St John’s wort and an oral contraceptive. personal communication. Clin Pharmacol Ther 67:451–457. Goodwin B. John’s wort is a 3A4 inducer (Moore et al. 200 mg bid for 1 week. Over the next 10 days. In the weeks following the addition of the St. and St.Gynecology. et al: St. 30 mg/day. this resulted in an unintended pregnancy. 2000). she discovered that she was pregnant (J. Clin Pharmacol Ther 74:525–535. One day. His primary care physician referred him to a dermatologist. May 2002). and Dermatology Case Vignettes 231 control. Wang Z. John’s wort: effect on CYP3A4 activity.

2002 Kivisto KT. These symptoms persisted for almost a week after completion of the first week of itraconazole. and by azole antifungal agents. even though the buspirone dosage had remained constant during the first week of itraconazole therapy. this significantly impaired the ability of 3A4 to efficiently metabolize the buspirone. 1997 von Moltke LL. Greenblatt DJ. However. Montvale. References Janssen Pharmaceutica: Sporanox (package insert). 1996 NYSTAGMUS A 32-year-old woman with a long-standing seizure disorder was doing well with phenytoin (Dilantin).3 µg/mL). Discussion This is an example of an inhibitor added to a substrate. and itraconazole is a strong competitive inhibitor of 3A4 (von Moltke et al. et al: Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole. J Clin Pharmacol 36:783–791. 1996). with no increase in his generalized anxiety. Kantola T. The patient followed these instructions faithfully. 17. Lamberg TS. the psychiatrist then instructed the patient to increase his buspirone by 5 mg/day until he resumed his usual dosage of 30 mg/day. 1997).232 Drug–Drug Interaction Primer the itraconazole regimen. she had been experiencing symptoms consistent with premenstrual dyspho- . Janssen Pharmaceutica. and tremor. norfluoxetine. et al: Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine. nausea. She instructed him to begin this buspirone taper on the first day of the second round of itraconazole. When the itraconazole was added. When she was consulted. and during the second round of itraconazole he experienced only mild drowsiness. Clin Pharmacol Ther 62:348– 354. NJ. resulting in a large increase in the blood level of buspirone. 300 mg/day (blood level. This led to the symptoms of sedation. After the patient completed the itraconazole regimen. Buspirone is a 3A4 substrate (Kivisto et al. the psychiatrist anticipated this interaction and gave buspirone dosing instructions that successfully took into account itraconazole’s half-life (64 ±32 hours) (Janssen Pharmaceutica 2002) and the magnitude of the interaction (itraconazole is reported to increase buspirone blood levels 5. she instructed him to decrease his buspirone dosing by 5 mg/day until he reached a dosage of 5 mg/day. 1997) for the second round of itraconazole therapy. When he reported these events to his psychiatrist. Schmider J.to 13-fold) (Kivisto et al.

Gynecology. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. Two days later. Fluoxetine (in concert with its active metabolite. S. A phenytoin level was 30. She tolerated the fluoxetine with no appreciable side effects. Armstrong. and drug interactions.3 µg/mL (K. even though the phenytoin dosage had not been changed (Jalil 1992. et al: Fluconazole-induced symptomatic phenytoin toxicity. 1999 Jalil P: Toxic reaction following the combined administration of fluoxetine and phenytoin: two case reports. 1994. Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. in this case). 1992 Mamiya K. 1999. Greenblatt DJ. Discussion This is an example of an inhibitor added to a substrate. but it was enough to produce significant signs of phenytoin toxicity. norfluoxetine) is a strong inhibitor of 2D6 and a moderate inhibitor of 2C9. Zenon GJ 3rd. J Neurosurg Psychiatry 55:412–413. et al: Human cytochromes and some newer antidepressants: kinetics. 1998). and 3A4 (Greenblatt et al. May 2002). Harmatz JS. von Moltke LL. Oncology. This increase in the phenytoin blood level was not as great in magnitude as it would have been with fluvoxamine. Epilepsia 39:1317–1323. Her gynecologist opted to start her on fluoxetine (Sarafem. to address this issue. et al: The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. where she was grossly ataxic and displayed vertical nystagmus on her neurological examination. leading to an increase in the phenytoin blood level. Thus. Ieiri I. However. Mamiya et al. 1993 . dizzy. von Moltke LL: Fluoxetine inhibition of phenytoin metabolism. personal communication. J Clin Psychopharmacol 14:375–376. and Dermatology Case Vignettes 233 ric disorder for the past year. Shader et al. 1994 Greenblatt DJ. Shimamoto J. Cozza. 2C19. the addition of fluoxetine significantly impaired the ability of 2C9 and 2C19 to significantly contribute to the metabolism of phenytoin. 1994). 1998 Shader RI. metabolism. she began to experience some new sedation within 5 days of starting the fluoxetine. 1994 Stevens JC. References Cadle RM. Rodriguez-Barradas MC.L. she was extremely groggy. Ann Pharmacother 28:191–195. and she eventually made an appointment to discuss this with her gynecologist. and nauseated and was seeing double. Stevens and Wrighton 1993).C. J Clin Psychopharmacol 19(suppl):23S–35S. 20 mg/day. J Pharmacol Exp Ther 266:964– 971. She had a friend transport her to the nearest emergency room.

which resulted in the patient’s remission following several previous failed trials (Ducharme et al. References Bottiger Y. 1999). Granvil CP. et al: Phenytoin-induced alteration in the N-dechloroethylation of ifosfamide stereoisomers. Griffiths L. Cancer Chemother Pharmacol 40:531–533. which did prevent further seizure activity. His oncologist was pessimistic. Toxicology 181–182:199–202. Bernstein ML. Phenytoin is an inducer of multiple enzymes. Baban D. In the midst of his treatment. 1998 Ducharme MP. 1997). 1997. However. Gibson et al. Ther Drug Monit 20:60–62. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. et al: Direct retroviral delivery of human cytochrome P450 2B6 for gene-directed enzyme prodrug therapy of cancer. Svensson JO. the patient went into a full remission following this trial. he developed seizures and he was placed on phenytoin (Dilantin). After this event. 1999. el-Sankary W. 2002 Kan O. and uridine 5′-diphosphate glucuronosyltransferase 1A4 (Bottiger et al. Seymour MA: Phenytoin autoinduction. Ther Drug Monit 21:171–174. 2002. 2C19. to a significant degree. 2001 . 2001). 3A4. Ifosfamide is. it was hypothesized that pretreatment with phenytoin led to the increased production of these more potent ifosfamide metabolites. Discussion This is an example of a substrate added to an inducer. Cyclophosphamide follows a metabolic path similar to that of ifosfamide (Williams et al. specifically including 2C9. with only partial or no success. 1997 Gibson GG. Cancer Gene Ther 8:473–482. 1998. he was given another chemotherapeutic trial that included ifosfamide (Ifex). Stahle L: Lamotrigine drug interactions in a TDM material. The likely induction of 2B6 by phenytoin probably increased the amount of 2B6 that was available to convert ifosfamide from the less-active parent compound to the more potently antineoplastic compounds (S)-2-DCE-ifosfamide and (S)-3-DCE-ifosfamide. Miller R. on the basis of the relative failure of the previous chemotherapeutic trials. 1999 Chetty M. Chetty et al. In this case. a pro-drug whose metabolic products possess much greater antineoplastic potency than the parent compound (Kan et al. Raucy 2003).234 Drug–Drug Interaction Primer OPTIMIZATION A 16-year-old with nonseminomatous testicular cancer had undergone several chemotherapeutic regimens. Ducharme et al.

Nguyen N. the kinetics are different. 200 mg/day. 2003 Williams ML. 2003). and inducers. with the result that the patient experienced her first seizure in more than 5 years. Wainer IW. 2001. Lamotrigine is primarily metabolized through phase II glucuronidation. Discussion This is an example of an inducer added to a substrate. Drug Metab Dispos 31:533–539. There may be more “crossover” metabolism among closely related glucuronidation enzymes than with P450 enzymes. Phase II glucuronidation seems to function in a manner analogous to P450 oxidative metabolism in that there are glucuronidation enzymes. Chirality 11:569–574. Events proceeded uneventfully until she had a grand mal seizure 3 weeks later (J. and so forth. Drug Metab Dispos 27:605–612. 2001). and the specific nature of the interactions is clearly different. Strassburg CP. more UGT1A4 was produced and thus available to more efficiently metabolize the lamotrigine. Buchholt JM. Oncology. and Dermatology Case Vignettes 235 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. 1999 CONTRACEPTIVE CONVULSION A 25-year-old woman with a long-standing seizure disorder had been seizure-free for 5 years while taking lamotrigine (Lamictal). specifically by the uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 enzyme (Hiller et al. She then began a serious relationship with a boyfriend. inhibitors.Gynecology. References Hiller A. there is an emerging appreciation for the importance and clinical relevance of the phase II component of drug metabolism. Uldall P. With the introduction of the ethinylestradiol. Ethinylestradiol is an inducer of UGT1A4 (Sabers et al. One study demonstrated that adding oral contraceptives in patients taking lamotrigine led to a mean 50% decrease in lamotrigine blood levels (Sabers et al. et al: Retigabine N-glucuronidation and its potential role in enterohepatic circulation. This led to a decrease in the blood level of lamotrigine. 1999). she started taking a standard oral contraceptive containing ethinylestradiol. 1999 Sabers A. et al: Lamotrigine plasma levels reduced by oral contraceptives. 2001 .R. Embree L. each of which has its own substrates. After the appropriate examinations and tests. et al: Enantioselective induction of cyclophosphamide metabolism by phenytoin. The analogy is not precise in several ways. and she visited her gynecologist in order to start taking oral contraceptives. Oesterheld. May 2002). However. Epilepsy Res 47:151–154. personal communication.

and upper back. 2003 RASH DECISION (II) The 25-year-old woman in the previous case (see “Contraceptive Convulsion”) eventually had her lamotrigine (Lamictal) dosage increased from 200 mg/day to 400 mg/day to compensate for the induction of the lamotrigine by her oral contraceptives. as they can be the precursor of a full Stevens-Johnson syndrome or toxic epidermal necrolysis. References Hiller A. Over the next several weeks. et al: Oral contraceptives reduce lamotrigine plasma levels. Drug Metab Dispos 27:605–612. Lamotrigine rashes generally warrant immediate discontinuation of this medication. with no recurrence of seizure activity. lamotrigine is primarily metabolized through phase II glucuronidation. As mentioned in the previous case. May 2002). 2001. red rash along her upper arms. This led to a precipitous increase in her blood level of lamotrigine. The patient agreed. et al: Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Nguyen N. until she developed a deep venous thrombosis in her right thigh during a transatlantic plane flight. and he instructed her to discontinue the lamotrigine and report to his office immediately so that he could examine the rash and plan how to proceed (J. Discussion This is an example of reversal of induction. specifically by the uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 enzyme (Hiller et al. 1999 . Two more years passed uneventfully. the patient felt more pervasively fatigued and forgetful. the “extra” UGT1A4 that had caused the lamotrigine to be more efficiently metabolized gradually “died off.R. personal communication. her gynecologist informed her that her oral contraceptives could have predisposed her to this event and that they should be discontinued at this point. 2003). however. and she promptly stopped taking the contraceptives. Neurology 61:570–571.” and UGT1A4 returned to its baseline level of functioning. she developed a diffuse. Strassburg CP. but she attributed this to more stress at work of late. Christensen J. shoulders. One month after discontinuing the contraceptives. as she had been previously advised. Ohman I. With the discontinuation of the ethinylestradiol. Oesterheld. After the patient had received appropriate acute treatment.236 Drug–Drug Interaction Primer Sabers A. She promptly informed her neurologist of this rash. 1999). which caused her fatigue and the emergence of a lamotrigine rash. and ethinylestradiol is an inducer of UGT1A4 (Sabers et al.

confusion. but because this seemed different she was not concerned. myoclonus. is a potent selective serotonin reuptake inhibitor (SSRI). However. 1994. and Dermatology Case Vignettes 237 Sabers A. One would expect the same syndrome to arise if buspirone (BuSpar) was added to an MAOI (Hyman et al. Uldall P.Gynecology. she was encountering difficulties with premenstrual mood swings and irritability. Fluoxetine. this patient’s condition stabilized after 1 week. 1994 Beasley CM Jr. norepinephrine. Discussion This is an example of a “substrate” added to an inhibitor. Zoloft. antipyretics. References Altamura AC. Five days into her treatment with Sarafem. Percudani M: Clinical pharmacokinetics of fluoxetine. Christensen J. epinephrine. Masica DN. and the liberal use of lorazepam (Ativan). et al: Oral contraceptives reduce lamotrigine plasma levels. Phenelzine is a monoamine oxidase inhibitor (MAOI). Ohman I. 60 mg/day. and dopamine). 1993). Beasley et al. and not her psychiatrist. Paxil. she experienced fever. where she was admitted and treated for a severe central serotonin syndrome. 1993). about these problems. Her brother brought her to the emergency room. The patient was certainly alert to avoid any medications like Prozac. Neurology 61:570–571. Her gynecologist diagnosed her with premenstrual dysphoric disorder and prescribed a medication called Sarafem (fluoxetine). Fortunately. J Clin Psychopharmacol 13:312–320. Heiligenstein JH. Clin Pharmacokinet 26:201–214. Moro AR. and as such it inhibits the breakdown of all monoamines (serotonin. Luvox. Epilepsy Res 47:151–154. 20 mg/day. Because all SSRIs greatly increase the availability of serotonin. although fatal outcomes have occurred with this combination of medications (Beasley et al. Oncology. with close observation. or Celexa. even under the trade name Sarafem. the central serotonin syndrome (Altamura et al. et al: Lamotrigine plasma levels reduced by oral contraceptives. Buchholt JM. 1995). and vomiting. nausea. 2001 Sabers A. et al: Possible monoamine oxidase inhibitor–serotonin uptake inhibitor interaction: fluoxetine clinical data and preclinical findings. 2003 TOO MANY COOKS IN THE KITCHEN A 31-year-old woman with atypical major depression was responding well to phenelzine (Nardil). She consulted her gynecologist. the combination of these effects led to a severe state of excessive serotonergic function. 1993 .

Arana G. and these are both P-glycoprotein substrates as well (Arima et al. Two days later. metronidazole does not raise the blood levels of either alprazolam (Blyden et al. 1996. 2E1. While in the hospital. Boston. 10. Rosenbaum J: Handbook of Psychiatric Drug Therapy. August 2002). Discussion This is (I believe) an example of a P-glycoprotein inhibitor added to a P-glycoprotein substrate. It is difficult to understand how a 3A4 inhibitor capable of raising carbamazepine blood levels could fail to raise levels of triazolobenzodiazepines. The gynecologist diagnosed her with bacterial vaginosis and prescribed metronidazole (Flagyl). Metronidazole has also been demonstrated to raise phenytoin blood levels (Blyden et al. she was restarted on carbamazepine (Tegretol). Ono et al. Staines et al. personal communication.8 µg/mL). Lin. MA. 2004). 2002). the patient was notably ataxic on the unit. both carbamazepine and phenytoin are P-glycoprotein substrates (Potschka et al. 2C8/9. Phenytoin is a substrate of 2C9 and 2C19 (Cadle et al. 2B6. 1988) or midazolam (Wang et al. A carbamazepine level drawn at that time was 27. and she reported feeling dizzy and very sedated.0 µg/mL (L. Carbamazepine is primarily a 3A4 substrate. Brown.238 Drug–Drug Interaction Primer Hyman S. 3rd Edition. . 2002. Also. metronidazole has been reported to raise the blood levels of both cyclosporine and tacrolimus blood levels (Herzig and Johnson 1999). 1994. Weiss et al. Some have hypothesized that metronidazole acts as a 3A4 inhibitor in elevating carbamazepine blood levels. However. Walters. so a gynecological consultation was arranged for the patient. 2001). 2000). 500 mg bid for 7 days. as though intoxicated. 1996). 2001. Mamiya et al. Spina et al. she complained about vaginal itching and burning. 2001. which are more “selective” 3A4 substrates than carbamazepine (Dresser et al. However. 800 mg/day (blood level. However. 2000). Little. Jones et al. K. Once admitted. 1988). with 1A2. 1998). to which her manic symptoms were responding. Yokogawa et al. and phase II metabolism (uridine 5′-diphosphate glucuronosyltransferase 2B7) making minor contributions to carbamazepine’s metabolism (Pearce et al. 1996) or diazepam (a 2C19 substrate) (Jensen and Gugler 1985. 1995 FLAGELLATED A 25-year-old woman with bipolar I disorder was hospitalized because of a manic episode precipitated by noncompliance with her medications. metronidazole fails to raise the blood levels of either tolbutamide (a 2C9 substrate) (Back and Tjia 1985.

Vakkalagadda GR. References Arima H. Ieiri I. and Dermatology Case Vignettes 239 From this evidence. Epilepsia 39:1317–1323. Zenon GJ 3rd. Br J Pharmacol 85:121–126. 2001 . Gugler R: Interaction between metronidazole and drugs eliminated by oxidative metabolism. J Clin Pharmacol 28:240–245. 1988 Cadle RM. Tjia JF: Inhibition of tolbutamide metabolism by substituted imidazole drugs in vivo: evidence for a structure-activity relationship. Drug Metab Dispos 30:1170– 1179. 2001 Back DJ. J Pharmacol Exp Ther 297:547–555. Xenobiotica 26:1155–1166. Johnson DW: Marked elevation of blood cyclosporin and tacrolimus levels due to concurrent metronidazole therapy. Nephrol Dial Transplant 14:521–523. et al: The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. et al: Putative active site template model for cytochrome P4502C9 (tolbutamide hydroxylase). Neuroreport 12:3557–3560. Rodriguez-Barradas MC.Gynecology. 2002 Potschka H. Leeder JS: Pathways of carbamazepine bioactivation in vitro. Clin Pharmacol Ther 37:407–410. 1996 Pearce RE. Fedrowitz M. et al: Contribution of P-glycoprotein to the enhancing effects of dimethyl-beta-cyclodextrin on oral bioavailability of tacrolimus. Scavone JM. The resulting increase in the absorption of carbamazepine probably explains the increase in the carbamazepine blood level following the addition of metronidazole. 1996 Mamiya K. where it would have been excreted rather than absorbed. et al: Fluconazole-induced symptomatic phenytoin toxicity. Drug Metab Dispos 24:260– 266. Loscher W: P-glycoprotein and multidrug resistanceassociated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. 1985 Jones BC. 1998 Ono S. the metronidazole likely decreased the activity of P-glycoprotein. 1999 Jensen JC. Greenblatt DJ: Metronidazole impairs clearance of phenytoin but not of alprazolam or lorazepam. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Spence JD. which led to less carbamazepine being extruded from enterocytes back into the gut lumen. Shimamoto J. Horne VA. Clin Pharmacokinet 38:41–57. 1985 Blyden GT. Hatanaka T. Hirayama F. I believe it is reasonable to regard metronidazole as a presumptive P-glycoprotein inhibitor. Oncology. Yunomae K. 2C19 and the 3A subfamily. et al: Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6. Miyazawa S. In that case. 1994 Dresser GK. 2000 Herzig K. I: characterization of human cytochromes P450 responsible for the formation of 2.and 3-hydroxylated metabolites. Hawksworth G. Ann Pharmacother 28:191–195.

Pharmacogenomics 1:157–158. Coughtrie MW. 20 mg/day. 1995). One of the major metabolites of tamoxifen (N-desmethyltamoxifen) is further converted to endoxifen (4-hydroxy-N-desmethyltamoxifen) primarily by the catalytic action of P450 2D6.240 Drug–Drug Interaction Primer Spina E. and she and her husband entered into marital therapy. Stearns et al. Silverman EK. Jin et al. Discussion This is an example of an inhibitor added to a substrate. Backman JT. 2005. Eur J Clin Pharmacol 56:555–559. 20 mg bid. Higashi Y. Burchell B: N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. She was a nonresponder to tamoxifen and died within the year. 1996 Staines AG. 2000 Weiss ST. Shimada T. The patient also received some individual counseling. Palmer LJ: Case-control association studies in pharmacogenetics. which he hoped would specifically address her symptom of insomnia. Furthermore this decreased conversion of tamoxifen. Her internist prescribed paroxetine (Paxil). Thus potent inhibitors of 2D6. 2001 Yokogawa K. The antineoplastic agent tamoxifen is actually a pro-drug. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Numerous studies have demonstrated that conversion of tamoxifen to endoxifen is impaired both by 2D6 genotypes that code for less active or inactive forms of this enzyme as well as by administration of exogenous 2D6 inhibitors (Borges et al. However. 2003). the patient’s cancer treatment was ultimately unsuccessful. and in the ensuing weeks he began to emotionally withdraw from her. Biochem Pharmacol 63:777–783. These developments led to her first major depressive episode. 2002 THE BEST LAID PLANS A 52-year-old woman has just been diagnosed with metastatic breast cancer. This multipronged approach was successful in helping the patient psychiatrically. will impair this conversion. J Pharmacol Exp Ther 311:1131– 1137. et al: Modulation of mdr1a and CYP3A gene expression in the intestine and liver as possible cause of changes in the cyclosporin A disposition kinetics by dexamethasone. 2004 Wang JS. 2006. et al: Effects of metronidazole on midazolam metabolism in vitro and in vivo. Endoxifen is a vastly more potent antiestrogenic compound than tamoxifen itself. Pisani F. in addition to surgery and radiation therapy. Upon sharing the news with her husband. whether through 2D6 . Clin Pharmacokinet 31:198–214. She was promptly placed on tamoxifen (Nolvadex). Kivisto KT. such as paroxetine (von Moltke et al. he responded in a minimally supportive manner.

Suman VJ.Gynecology. Johnson MD. Since there is a wide array of antidepressants from which to choose. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. 2003 von Moltke LL. Desta Z. Knox SK. References Borges S. J Natl Cancer Inst 97:30–39. J Clin Psychopharmacol 15:125–131. Li L. et al: Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. has been found to increase the risk of and decrease the time to breast cancer recurrence (Geotz et al. 2002). Desta Z. 1995 . Court MH. Stearns V. Breast Cancer Res Treat 101:113– 121. et al: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. Greenblatt DJ. and Dermatology Case Vignettes 241 poor metabolizer status or administration of a potent 2D6 inhibitor. and tamoxifen metabolism during adjuvant breast cancer treatment. et al: The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. a prudent approach would be to avoid administering compounds that significantly inhibit 2D6 to patients taking tamoxifen. antidepressant use. 2007 Jin Y. 2005 Stearns V. J Natl Cancer Inst 95:1758–1764. 2006 Goetz MP. Rae JM. et al: CYP2D6 genotype. Oncology. Clin Pharmacol Ther 80:61–74.

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The growing range of treatment options has made treating patients more complex. The Academy of Psychosomatic Medicine. Cozza KL: “An Overview of Psychotropic Drug-Drug Interactions.Appendix A AN OVERVIEW OF PSYCHOTROPIC DRUG– DRUG INTERACTIONS Neil B.D. Used with permission. Copyright 2005. However. 2005. The array of available psychopharmacologic agents has expanded tremendously over the last 20 years. To para- This appendix is reprinted from Sandson NB. 243 . Armstrong SC. Cozza. Kelly L. Choosing appropriate agents for patients and making shrewd changes when faced with medication intolerance or treatment resistance occupy the bulk of most psychiatrists’ pharmacological concerns. M.D. M. Scott C. Sandson.D. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.” Psychosomatics 46:464–494. Armstrong. It is a formidable challenge to remain familiar with the evolving evidence base. and it should precede the quest for efficacy. another domain of psychopharmacology is critical to best practice. M.

For example. and mood stabilizers. one agent causes the blood level of another agent to be raised or lowered. Drug–drug interactions are actually quite commonplace1–5 and are responsible for considerable patient morbidity and mortality. and subsequent health care costs.12. for many psychiatrists.16 However.9–11 Yet.6–8 A growing and sobering evidence base implicates drug–drug interactions as a major contributor to hospital admissions.18. Pharmacodynamic interactions represent the synergy or antagonism of each drug’s effects at target receptors. including alterations in drug metabolism. excretion.15. it is incumbent on clinicians to “First. urinary retention. the synergistic anticholinergic activity of amitriptyline combined with benztropine can produce constipation. drug–drug interactions are rarely foremost in the minds of otherwise excellent clinicians. An ideal starting point for psychiatrists is to examine drug–drug interactions involving the familiar psychotropic agents that are most relevant to their practices. antipsychotics. by our relatively primitive ability to detect drug–drug interactions. which appropriately examine the issue of drug–drug interactions across medical disciplines. do no harm. concerned physicians are eager to know more. Most current drug–drug interaction software programs have problems with both sensitivity and specificity14 and are not especially user friendly. and other related difficulties.13 However. practitioners often fall well short of that dictum. There are some excellent publications on this topic. and distribution. heat stroke. avoidable medical complications.17 Another familiar example is central serotonin syndrome. absorption. This disconnection is explained. this wide range presents an overwhelming flood of information. This review focuses on intrapsychotropic drug–drug interactions involving antidepressants. especially where drug–drug interactions are concerned.244 Drug–Drug Interaction Primer phrase Hippocrates.” Unfortunately. Pharmacokinetic drug– drug interactions may occur through multiple mechanisms. but it can be a daunting enterprise.4. treatment failures. which results from the combination of a monoamine oxidase inhibitor (MAOI) with a selective serotonin reuptake inhibitor (SSRI). .19 In pharmacokinetic interactions. in part. TYPES OF DRUG–DRUG INTERACTIONS The two major varieties of drug–drug interactions are pharmacodynamic interactions and pharmacokinetic interactions. Grappling with the entire array of drug–drug interactions is a worthwhile goal for anyone who prescribes medications. They often promote a therapeutic paralysis that is almost as undesirable as an ignorance of drug–drug interactions. as understanding of the importance of drug–drug interactions grows.5.

22 olanzapine. which is predominantly concerned with metabolic alterations. including lamotrigine.). nortriptyline is metabolized primarily by P450 2D6. and 3A4. Phase II conjugation generally serves as a metabolic capstone.An Overview of Psychotropic Drug–Drug Interactions 245 Pharmacodynamic drug–drug interactions are usually intuitively straightforward. The most prominent is the cytochrome P450 system. 2C9. thus producing increased blood levels of those substrates.25 is handled solely or primarily by the UGTs. the contribution of phase II metabolism to drug–drug interactions is typically not as significant as that of phase I metabolism. 2E1. Pharmacokinetic drug–drug interactions are much more difficult to anticipate. The P450 system is a family of mostly hepatic enzymes that perform oxidative (phase I) metabolism. whereas induction usually requires several days to 2 or more weeks to exert a meaningful effect on drug metabolism. and it is therefore a substrate of this enzyme. If one has a basic sense of a drug’s mechanism of action and receptor occupancies. UGTs are identified by a number-letter-number scheme (1A1. 2B6. etc. A related metabolic system implicated in drug–drug interactions is phase II conjugative metabolism. Most of the challenge posed by drug–drug interactions rests in the pharmacokinetic domain. and inducers. leading to increased metabolism of substrates of those P450 enzymes. METABOLIC ENZYMES Several key enzymatic systems are frequently involved in pharmacokinetic drug–drug interactions. For this reason. these interactions can often be predicted and avoided. . 1A4. Like the P450 system. 2B15. the major enzymes in this group are 1A2. Phase I enzymes usually perform the bulk of the metabolic workload.23 and many narcotic analgesics. 2B7. Enzymatic inhibition is usually immediate. inhibitors. However. the metabolism of several agents. Conversely.24. and each enzyme has a unique array of substrates. rendering substances that have already undergone phase I oxidation more hydrophilic and thus more readily excretable. 2D6. 2C19. The most prominent phase II enzymatic family is the uridine 5′-diphosphate glucuronosyltransferases (UGTs). inducers cause an increase in the production of particular P450 enzymes. P450 substrates are agents that are metabolized by particular P450 enzymes. A familiarity with prominent UGT inhibitors and inducers is thus important in order to anticipate and prevent drug–drug interactions involving these agents. 20. For instance. Specific P450 enzymes are named by number-letter-number sequences. Knowing how a drug accomplishes its intended therapeutic effect rarely confers any knowledge of its kinetic parameters or of the ways these parameters will interact with those of another drug.21 P450 inhibitors impair the ability of specific P450 enzymes to metabolize their target substrates.

For instance.28 Distribution issues are actually somewhat infrequent for psychotropics.27. or from the capillaries of the blood-brain barrier back into the bloodstream.29.26 Drugs that affect renal excretion can alter the blood level of lithium. and P-glycoprotein systems are available from multiple published and online sources. Like the P450 and UGT metabolic systems. P-glycoprotein functions by extruding substrates from the cytosol of enterocytes back into the gut lumen. extruding transporter. P-glycoprotein is an ATP-dependent. It also lines the capillaries of the blood-brain barrier. and distribution. Alterations in gastrointestinal pH. and P-glycoprotein inducers decrease the levels of P-glycoprotein substrates. the P-glycoprotein transporter has substrates. P-glycoprotein inducers increase the amount of active P-glycoprotein and thus lead to more extrusion and excretion of P-glycoprotein substrates. inhibitors. An exhaustive set of P450 tables may be found in the Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s. The list of known P-glycoprotein substrates. and the rate of bowel motility are only a few of the factors that can affect absorption. UGTs.30 CURRENT PRACTICAL RESOURCES Tables of drug–drug interactions involving the P450. and inducers is already quite large and is growing with each passing month. P-glycoprotein is also found in the cells lining renal tubules. the absorption of ziprasidone is much greater when it is consumed with food. It resides in the plasma membrane of enterocytes that line the gut lumen. excretion. P-glycoprotein inhibitors antagonize this process and lead to greater retention and absorption of P-glycoprotein substrates.246 Drug–Drug Interaction Primer P-GLYCOPROTEINS Of the nonmetabolic systems that mediate pharmacokinetic drug–drug interactions. where it constitutes one of the core elements preventing various substances from gaining access to the CNS. and inducers. the P-glycoprotein transporter is emerging as a critically important contributor. P-Glyco- . OTHER PHARMACOKINETIC PROCESSES Other pharmacokinetic drug–drug interactions are caused by alterations in absorption (not relating to P-glycoprotein). The net effect of this activity is that Pglycoprotein inhibitors increase the blood levels of P-glycoprotein substrates. inhibitors. and in this location it is an important regulator of drug absorption and bioavailability. although the blood level of unbound or free valproate can be significantly increased by daily antipyretic doses of aspirin. UGT. the presence or absence of food.

42. 2B6.43.47. 2C19.37. 2C19. M...47 Sertraline. 2nd Edition. SPECIFIC PHARMACOKINETIC FEATURES OF PSYCHOTROPIC AGENTS Antidepressants SSRIs Citalopram.An Overview of Psychotropic Drug–Drug Interactions 247 proteins. and 3A4.36 Escitalopram.51 It is also both a substrate and an inhibitor of P-glycoprotein.35 Citalopram is a substrate of P-glycoprotein.41.31.mhc.40 and mildly to moderately inhibit 1A2.edu/flockhart/.34 as evidenced by its ability to increase blood levels of desipramine and metoprolol. as well as very complete UGT and P-glycoprotein tables. It is a potent inhibitor of 1A2 and 2C19. 2C9. Sertraline and its mildly active metabolite desmethylsertraline are substrates of multiple P450 enzymes. much like cimetidine. 2D6.57 Sertraline inhibits 2D6 in a dose-dependent manner.45. www.39 Together.D (American Psychiatric Publishing.15. At doses under 100 mg/day. 2D6. provides an excellent P450 table online at http:// medicine. It is also a P-glycoprotein inhibitor. which contains a P450 table tailored for psychiatrists.34.D.52 Paroxetine.D. M. Fluvoxamine is primarily metabolized by P450 1A2 and secondarily by 2D6. Dr.44 It is also both a substrate and an inhibitor of P-glycoprotein. M. The pharmacokinetic features of escitalopram are basically the same as those of citalopram. Citalopram is metabolized primarily by P450 2C19.45. they potently inhibit 2D634.50. Fluoxetine and its active metabolite norfluoxetine are together metabolized by P450 2C9. 2D6.45. Inc. and 3A4. sertraline may only mildly inhibit 2D6.54. M. 56. Paroxetine is primarily metabolized by P450 2D6 and secondarily by 3A4.D.com/Cytochromes.. 2C9. 48. At doses above 150 mg/day.41–46 Fluoxetine can reasonably be considered a P450 pan-inhibitor. 2D6 inhibition may become . 2003). David Flockhart. by Kelly Cozza. and Jessica Oesterheld.31–33 It is likely a mild to moderate inhibitor of 2D6. Oesterheld is the coauthor of a website.53 It is a potent inhibitor of 2B6 and 2D6 34.iupui. and3A4.49 It is a pan-inhibitor like fluoxetine.48. Scott Armstrong. and 3A4.42.38 Fluoxetine (norfluoxetine).50 and a mild to moderate inhibitor of 2B6.47 Fluvoxamine.55 but only a mild inhibitor of other P450 enzymes..

are primarily substrates of P450 2D6. and 3A4 and hydroxylation by 2D6.85 Duloxetine. clomipramine.91 but it is also a potent inhibitor of P450 2A692.86.78.59–61 Possibly unique among the SSRIs. The metabolism of tertiary-amine TCAs.89 It has no significant inhibitory or inductive capabilities. including metabolism by P450 1A2.21. is much more complex than that of the secondary-amine TCAs.88.91 Tranylcypromine is also a substrate of MAOA.73– 77 UGT1A4 also makes a minor contribution to the metabolism of tertiary amine TCAs. Duloxetine is metabolized by P450 1A2 and 2D6.62 Sertraline is also a P-glycoprotein inhibitor.90 MAOIs.19. 2C19.93 (a minor P450 enzyme) and a mild to moderate inhibitor of 1A2.68 These TCAs also appear to be both substrates and inhibitors of P-glycoprotein. sertraline also appears to be a specific and potent inhibitor of UGT1A4.69–71.63.81 Other Antidepressants Bupropion. Tertiaryamine TCAs undergo both demethylation to secondary amine TCAs through the action of 1A2. and there is some evidence that amitriptyline and imipramine are mild inhibitors of 2C19.58 Sertraline is also a moderate inhibitor of 2B6 and 2C1942. Secondary-amine tricyclic antidepressants (TCAs).34. Phenelzine is a substrate of monamine oxidase A (MAOA) and lacks any significant P450 inhibitory or inductive capabilities.44 and a mild inhibitor of 1A2 and 3A4.86 It is a moderate inhibitor of 2D6. considered without the contribution of the secondary-amine metabolites. imipramine.67.94 .248 Drug–Drug Interaction Primer moderate to potent.18. including desipramine. 2D6. and protriptyline.68 These TCAs also appear to be inhibitors of P-glycoprotein. 23. as evidenced by the ability of 25 mg/day of sertraline to double the blood level of lamotrigine. and 3A4. Mirtazapine has multiple metabolic pathways. tends to be only mild. and 2E1. including amitriptyline. trimipramine.83 It is a moderate to potent inhibitor of 2D6.63–66 They are also moderate 2D6 inhibitors.34.41.37.87 Mirtazapine.65. and doxepin.47 Tricyclic Antidepressants Secondary-amine tricyclic antidepressants. Bupropion is primarily metabolized by P450 2B6. and nortriptyline has been demonstrated to be a P-glycoprotein substrate. 2C19. nortriptyline.84.69–72 Tertiary-amine TCAs.82. which performs hydroxylation on these compounds.20.79 Tertiary-amine TCA inhibition of 2D6.80.

114 It appears to be an in vitro P-glycoprotein substrate of weak affinity.101 Trazodone.An Overview of Psychotropic Drug–Drug Interactions 249 Nefazodone. phenothiazines are metabolized primarily by P450 2D6. As a general rule.46.113 Haloperidol. Atypical Antipsychotics Aripiprazole.23.67 It is also both a substrate and a mild inhibitor of P-glycoprotein.115 Pimozide.80 Because of its arrhythmogenic potential. it is initially an acute inhibitor and later a chronic inducer. 118 It lacks any known inhibitory or inductive capabilities.52. trazodone relies primarily on P450 3A4 for its metabolism.103.109 Most of these agents display moderate to potent 2D6 inhibition. This agent.117 It is also an inhibitor of P-glycoprotein.52. and it is a mild 2D6 inhibitor.95 One of these is metachlorophenylpiperazine (mCPP). relying principally on P450 3A4 and phase II metabolism (not yet elucidated).47 Antipsychotics Typical Antipsychotics Phenothiazines. although several typical agents are P-glycoprotein substrates as well. this agent has a relatively low therapeutic index. and one of the principal metabolites resulting from its metabolism by 3A4 is mCPP. Nefazodone is primarily metabolized by P450 3A4 into three major metabolites.112.96 an acutely anxiogenic.102 Trazadone is also an inducer of P-glycoprotein. Aripiprazole’s metabolism is roughly equally divided between P450 2D6 and 3A4.112. with secondary contributions from 2D6 and 1A2. Venlafaxine’s metabolism relies primarily on P450 2D6.79.107. Pimozide is metabolized primarily by P450 3A4. with a secondary contribution by 1A2. Haloperidol’s metabolism is quite complex. of P-glycoprotein.111 As a class. partial serotonin agonist that relies on 2D6 for its metabolism. a partial dopamine agonist.115 One of haloperidol’s metabolites is a potent 2D6 inhibitor.103–107 with frequent contributions from 1A2 and phase II metabolism.100 Also. they appear to be P-glycoprotein inhibitors.108 3A4 makes only a minor contribution to the metabolism of most phenothiazines. displays more avid binding to the dopamine D2 receptor than any other antipsychotic.117 It is a potent inhibitor of 2D6 and moderate inhibitor of 3A4. Like nefazodone.110.106.101 Venlafaxine.97–99 Nefazodone is a potent inhibitor of 3A4. 116 Haloperidol is also a P-glycoprotein inhibitor.119–122 .

150 In the presence of a UGT1A4 inhibitor such as valproate.111.138–140 It is also likely an inhibitor of 2C19.22.52 Quetiapine. Quetiapine is mostly metabolized by P450 3A4. this P450 pathway leads to the generation of toxic metabolites. ziprasidone is principally metabolized by aldehyde oxidase. 2E1. and phase II metabolism (UGT 2B7) serve as minor pathways. 128.50.129 It is also an in vitro P-glycoprotein substrate of moderate to strong affinity 112 and a P-glycoprotein inhibitor. serve as a secondary pathway. 3A4.137. although 3A4 also makes a significant contribution. Olanzapine is mostly metabolized by P450 1A2 and UGT 1A4. 2B6.141–143 Carbamazepine is a potent inducer of 3A4. 2C8/9.250 Drug–Drug Interaction Primer Clozapine.135–137 It is both a substrate and an inhibitor of P-glycoprotein. 26. 112 Risperidone acts as a mild to moderate 2D6 inhibitor.126 This agent has a fairly low therapeutic index. 2C8/9.146–149 Lamotrigine Lamotrigine is primarily metabolized by UGT1A4.123–125 It appears to be an in vitro P-glycoprotein substrate of weak affinity. 2B6. and UGT1A4.134 It lacks any known inhibitory or inductive capabilities.127 It is also an in vitro Pglycoprotein substrate of low to moderate affinity112 and a P-glycoprotein inhibitor.133 Ziprasidone. including 2C9/19.145 and it also induces 1A2. 23. a greater proportion of lamotrigine is metabolized through this P450 metabolic . although its inhibitory capability is unlikely to be clinically significant.144. with P450 3A4 serving as a secondary pathway. although 1A2. as evidenced by carbamazepine’s ability to increase blood levels of both phenytoin and clomipramine. In healthy adults. Olanzapine.52 Risperidone.23 although one or more P450 enzymes. with 2D6 serving as a minor pathway.111. Most of risperidone’s metabolism occurs through P45 2D6.134. 2D6. 130–132 It is also an in vitro P-glycoprotein substrate of moderate to strong affinity. However.112 It is also a known mild inhibitor of 2D6. Mood Stabilizers Carbamazepine Carbamazepine is primarily metabolized by P450 3A4. and UGT 1A3/4. not yet well characterized. Clozapine is principally metabolized by P450 1A2 with numerous secondary pathways.

159–162 Topiramate Topiramate is primarily renally excreted. 3A4. 1A9.158 It induces multiple enzymes. Its hepatic metabolism is mostly governed by phase II enzymes with a minor phase I contribution.151 Lithium Lithium is purely renally excreted.170 .157 It is also a P-glycoprotein substrate.164 It is likely to be a P-glycoprotein substrate. even when low dosages of lamotrigine are used.167 and a mild inducer of 3A4. and UGTs 1A1 and 1A4.172 It is a moderate inhibitor of 2C9.151. including 1A4. UGT1A6. including 2B6. with no hepatic metabolic component.175 It is unclear if valproate has any meaningful inductive capabilities.153 and a moderate inducer of UGT1A4.171 as well as epoxide hydrolase.149.173 It also inhibits multiple UGTs. Both oxcarbazepine and MHD are metabolized in part through phase II glucuronidation.11-epoxide).169 Valproate Valproate’s metabolism is exceedingly complex. the enzyme that metabolizes the principal metabolite of carbamazepine (carbamazepine-10. 1A9. 2C9/19.137.168.156 with minor contributions from multiple UGT1A family enzymes.174.152 Oxcarbazepine is a mild inducer of 3A4. involving multiple phase I and II pathways (P450 2A6 and 2C9170.155.141 Phenytoin Phenytoin is primarily a substrate of P450 2C9 and 2C19. It lacks any inhibitory or inductive capabilities. and 2B15. 2B7.147. and 2B7171) as well as β-oxidation.154 MHD is an inhibitor of 2C19.149. Some weak autoinduction (at UGT1A4) has been noted. This effect helps to explain why the combination of valproate and lamotrigine is associated with a greater incidence of both Stevens-Johnson syndrome and toxic epidermal necrolysis.141. Oxcarbazepine Oxcarbazepine is quickly metabolized to an active monohydroxyoxcarbazepine (MHD) metabolite by the action of arylketone reductase. leading to production of these toxic metabolites. neither of which has been well characterized.An Overview of Psychotropic Drug–Drug Interactions 251 pathway.163.165 It is an inhibitor of 2C19166. Agents that induce the metabolism of valproate through 2C9 and 2A6 (such as phenytoin) lead to the increased production of the hepatotoxic 4-ene-valproate metabolite.

For instance. along with some drug–drug interactions involving other psychotropic agents (anxiolytics. caffeine. The only reasonable approach lies in the realm of computers. Table A–3 lists significant drug–drug interactions involving mood stabilizers and other psychotropic agents. the combination of fluoxetine and risperidone will lead to an average increase of 75% in the blood level of the risperidone active moiety (the combined concentrations of risperidone and its equipotent 9-hydroxy-risperidone metabolite). 28. Lithium and valproate are notable exceptions to this generalization.178.180 Hence. who will be harmed by drug–drug interactions. they also make it clear that the broad range of information on drug–drug interactions severely tests the limits of human recall. these interactions involve substrate-inhibitor pairings. etc. the combination of fluoxetine and quetiapine reliably produces increases in the peak and trough concentrations of quetiapine that are statistically significant but usually not clinically significant. in which substrate blood levels are increased.182 By virtue of their special importance. create drug– drug interactions with numerous psychotropic agents. they are often involved as inducers of the metabolism of other agents. Because several of these agents are anticonvulsants.252 Drug–Drug Interaction Primer DISCUSSION Table A–1 lists significant drug–drug interactions involving antidepressants and other psychotropic agents. only those interactions that are both reasonably frequent and problematic are included.176 Table A–2 lists significant drug–drug interactions involving antipsychotics and other psychotropic agents.177 and lithium plus fluoxetine can yield a central serotonin syndrome. In contrast. selected examples of such interactions have been included in Table A–4.). Some ubiquitous nonpsychotropic agents/influences. the antipsychotic agents generally play the role of substrates in substrate-inhibitor and/or substrate-inducer pairings. both of these combinations are common and well tolerated the vast majority of the time. However. “Classic” drug–drug interactions include those between lithium and diuretics28. It is simply not practical to insist that memorization of all the permutations of drug–drug interactions become the standard of care. Although reviews such as this one may prove helpful to the clinician. In all of these drug–drug interactions tables.181 and between acetylsalicylic acid and valproate. In general.179 However. recognition that the clinician cannot be expected to remember all of these details is small consolation to our patients. In these interactions. the combination of lithium and haloperidol can produce an encephalopathic state. We urgently need programs . such as tobacco (smoked) and oral contraceptives containing ethinylestradiol. For instance. none of these drug–drug interactions are included in the tables.

) and refer to them whenever a drug– drug interaction is suspected. Become an “expert” on the drugs you prescribe most frequently. The more complete a drug–drug interactions database is. herbal . 183. Second. a drug–drug interaction that produces a significant increase in the blood level of.184 Accordingly. Pay special attention to agents that have a low therapeutic index (the lethal dose for 50% of the population divided by the effective dose for 50% of the population [LD50/ED50]). it encourages a mindset in which one does not rely solely on personal powers of recall to make clinical decisions. the more nonspecific the warnings become. books. is unlikely to yield a truly dangerous outcome. computer programs. for instance. In the interim. 2. However. over-the-counter remedies. the number of psychotropic agents is fairly modest. tables. Most of the more recently developed and released psychotropics are safer in overdose than their predecessors. and this characteristic increases obstructions to physicians’ workflow. for the sake of our patients. etc. Acquiring a detailed understanding of the drug–drug interactions involving these agents will largely prevent such adverse events. repeated use of these resources when dealing with actual patients in real situations is the best way to become familiar with clinically relevant drug–drug interactions. First. but development of such tools presents considerable challenges. In absolute terms. 4. 3.90 However. Patients should be encouraged to keep a current list of all medications. we must somehow grapple with this imposing and evolving body of information. In that spirit. it is manifestly dangerous to our patients. best line of defense in the prevention of drug–drug interactions. A physician who makes frequent use of auxiliary resources is a safer clinician. Educate your patients to be their own last. Consult resources frequently. agents such as TCAs and lithium are potentially lethal in overdose. This vigilance serves two functions. It is both reasonable and practical for clinicians to acquire a solid knowledge of the drug–drug interactions involving this specific subset of agents. and most psychiatrists prescribe a limited group of 10–20 drugs far more often than they prescribe the remaining psychotropic agents. drug–drug interactions that produce significant increases in the blood levels of these agents can lead to severe morbidity and mortality. Although such reliance is consistent with typical modes of practice and the standard of care. Thus. the following practical drug–drug interaction “survival tips” are offered for the busy clinician: 1. programs that ideally optimize completeness and efficiency might not become available for decades.An Overview of Psychotropic Drug–Drug Interactions 253 that will supply information on drug–drug interactions in a manner that is both complete and efficient. Gather reliable references (articles. mirtazapine.

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276 TABLE A–1. Significant drug–drug interactions involving antidepressants Antidepressant and interacting drug Bupropion Carbamazepine Duloxetine Pharmacokinetic results Decreased level of bupropion192. constipation.193 Increased level of duloxetine Increased level of bupropion85 Increased level of bupropion85 n/a Mechanisms Induction of P450 2B6 by carbamazepine83. combined with norepinephrine reuptake inhibition by bupropion Inhibition of P450 2D6 by bupropion84.19.86.87 Inhibition of P450 2B6 by fluoxetine plus norfluoxetine42.98 Clinical consequences Comments Fluoxetine Possible loss of therapeutic efficacy Dry mouth.83 Decreased metabolism of norepinephrine by MAOIs.147 Inhibition of P450 2D6 by bupropion84. sedation.85 Theoretical concern Potentially fatal Drug–Drug Interaction Primer Nefazodone Increased level of metachlorophenylpiperazine (mCPP) Acute dysphoric anxiety Theoretical concern . Theoretical concern fatigue.83 Inhibition of P450 2B6 by fluvoxamine42. increased sweating Increased risk of seizures Theoretical concern Fluvoxamine MAOIs Increased risk of seizures Increased risk of hypertensive crisis18.

37.107 Clinical consequences Increased risk of seizures Increased extrapyramidal side effects (EPS) and other side effects Comments Theoretical concern Phenytoin Sertraline TCAs Decreased level of bupropion Increased level of bupropion85 Increased levels of TCAs84.33.83 Inhibition of P450 2D6 by bupropion84.194 Mechanisms Inhibition of P450 2B6 by paroxetine42. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Paroxetine Phenothiazine antipsychotics Pharmacokinetic results Increased level of bupropion85 Increased levels of phenothiazine antipsychotics85.85 Induction of P450 2B6 by phenytoin83.134.65.198 277 . escitalopram Carbamazepine Decreased levels of citalopram and of escitalopram196 Induction of P450 3A4 by carbamazepine32.83 Inhibition of P450 2D6 by bupropion21.137.64.104.197.147 Inhibition of P450 2B6 by sertraline42.195 Combination of bupropion with mesoridazine or thioridazine can increase arrhythmogenic potential Possible loss of therapeutic Theoretical concern.84.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1. efficacy but likely Increased risk of seizures Theoretical concern Increased arrhythmia risk and anticholinergic symptoms Possible loss of therapeutic efficacy Citalopram. 145.75.103.

19.107 Clinical consequences Central serotonin syndrome18. combined with serotonin reuptake inhibition by citalopram and by escitalopram Inhibition of P450 2D6 by citalopram and by escitalopram31.278 TABLE A–1.34.103.198 Combination of citalopram or escitalopram with mesoridazine or thioridazine can increase arrhythmogenic potential (theoretical concern) Possible loss of therapeutic Theoretical concern efficacy Drug–Drug Interaction Primer . Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pharmacokinetic results Mechanisms Decreased metabolism of serotonin by MAOIs. 159–161.38 Comments Potentially fatal Citalopram.104. escitalopram (continued) MAOIs n/a Phenothiazine antipsychotics Increased levels of phenothiazine antipsychotics Increased EPS and other side effects Phenytoin Decreased levels of citalopram and escitalopram Induction of P450 3A4 and 2C19 by phenytoin32.35.33.

37.87 Clinical consequences Comments Secondary-amine Increased levels of TCAs secondary-amine TCAs35.38 Duloxetine Bupropion Increased level of duloxetine Carbamazepine Fluoxetine.146 Inhibition of P450 2D6 by Dry mouth. sedation. paroxetine Fluvoxamine Decreased level of duloxetine Increased level of duloxetine87 Increased level of duloxetine87 Increase in the QT interval Theoretical concern without an increase in the level of pimozide35. increased sweating Possible loss of therapeutic Theoretical concern Induction of P450 1A2 by efficacy carbamazepine37.86 increased sweating Inhibition of P450 1A2 >> 2D6 Dry mouth.64. Theoretical concern fatigue. by fluvoxamine34. or by paroxetine34.38 Increased arrhythmia risk Theoretical concern and anticholinergic symptoms Dry mouth. fluoxetine plus norfluoxetine fatigue. constipation.86 fatigue. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pimozide Pharmacokinetic results n/a Mechanisms Unclear pharmacodynamic effect Inhibition of P450 2D6 by citalopram and by escitalopram21. constipation.48.40. sedation.86.34.195 Inhibition of P450 2D6 by bupropion84. increased sweating 279 . constipation.31. sedation.54.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.

103.280 TABLE A–1. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments Duloxetine (continued) MAOIs n/a Paroxetine Increased level of duloxetine Increased levels of phenothiazine antipsychotics87 Phenothiazine antipsychotics Central serotonin Decreased metabolism of Potentially fatal serotonin and norepinephrine syndrome and/or hypertensive crisis18.64. interaction of duloxetine paroxetine and fluoxetine.104. combined with serotonin and norepinephrine reuptake inhibition by duloxetine See information for interaction See information for of duloxetine and fluoxetine.75.87 by MAOIs.65.107 side effects duloxetine with mesoridazine or thioridazine can increase arrhythmogenic potential Inhibition of P450 2D6 by duloxetine21.19.86.195 Increased arrhythmia risk and anticholinergic symptoms Drug–Drug Interaction Primer TCAs Increased levels of TCAs87 . paroxetine Inhibition of P450 2D6 by Increased EPS and other Combination of duloxetine86.

60.46.135.40. 40.83 Inhibition of multiple P450 enzymes (3A4.124 as well as P-glycoprotein47. 2D6. anticholinergic symptoms. and 3A4. tremor. seizure risk. increased sweating 281 .44.34. 2C9/19.46. sedation. 2C9)41–43. nausea. Clozapine Increased level of clozapine201 Increased sedation.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1. 86 Clinical consequences Increased risk of seizures Comments Theoretical concern Carbamazepine Ataxia. 43.41. 1A2. dysarthria. sedation. Clozapine levels typically increase by roughly 50% with this combination Duloxetine Increased level of duloxetine87 Dry mouth.138 by fluoxetine plus norfluoxetine Inhibition of P450 1A2.200 and P-glycoprotein47. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Fluoxetine Bupropion Pharmacokinetic results Increased level of bupropion85 Increased level of carbamazepine199 Mechanisms Inhibition of P450 2B6 by fluoxetine plus norfluoxetine42.123. fatigue. 2B6. etc. diplopia.112 (weak contribution) by fluoxetine plus norfluoxetine Inhibition of P450 2D6 by fluoxetine plus norfluoxetine34.60. etc. constipation.

98 Inhibition of both P450 2C9/19 43. etc.40. ataxia.156 and P-glycoprotein47.60 Inhibition of P450 2D6/ 3A434.46.40.202 Comments Potentially fatal Fluoxetine (continued) MAOIs n/a Nefazodone Increased level of mCPP203 Increased level of phenytoin204 Acute dysphoric anxiety Phenytoin Nystagmus.130 and P-glycoprotein47.112 by fluoxetine plus norfluoxetine Clinical consequences Central serotonin syndrome178. combined with serotonin reuptake inhibition by fluoxetine plus norfluoxetine Inhibition of P450 2D6 by fluoxetine plus norfluoxetine34.97.46.60.155. Increased EPS and One known case arrhythmogenic potential of serious bradycardia205 EPS.158 by fluoxetine plus norfluoxetine Inhibition of P450 1A2 and 3A4 by fluoxetine plus norfluoxetine (probably)41. tremor. nausea.44. dysarthria. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pharmacokinetic results Mechanisms Decreased metabolism of serotonin by MAOIs. sedation. increased prolactin Average increase in the ‘‘risperidone active moiety’’ of roughly 75% Drug–Drug Interaction Primer Pimozide Increased level of pimozide (probably) Increased level of risperidone176 Risperidone .68.282 TABLE A–1.

Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug TCAs Pharmacokinetic results Increased levels of TCAs20.50. tremor.209 Inhibition of multiple P450 Increased arrhythmia risk enzymes21.34.212 and 2) decreased level 2C9)42. etc. symptoms 70. sedation. nausea.43.44.210 and P-glycoprotein47.43.40.40. 2B6.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1. 1A2. and anticholinergic 75–77 and P-glycoprotein36.52. and side effects 3A4)34.41.146 Increased risk of seizures Ataxia. 2) induction of P450 1A2 by carbamazepine48.206.112 by fluoxetine plus norfluoxetine Combining with mesoridazine.60. carbamazepine211.69. diplopia.51. thioridazine. 2D6.48.103–105.47.138 by fluvoxamine.200 of fluvoxamine and P-glycoprotein47.41.52.107.207 Mechanisms Clinical consequences Comments Typical antipsychotics Increased levels of most typical antipsychotics194.46.208 by fluoxetine plus norfluoxetine Inhibition of multiple P450 Increased EPS and other enzymes (1A2.45. 283 .60. dysarthria.135.75. or pimozide can increase arrhythmogenic potential Theoretical concern Decrease in fluvoxamine levels is a theoretical concern Fluvoxamine Bupropion Carbamazepine Increased level of Inhibition of P450 2B6 by bupropion85 fluvoxamine42.83 1) Inhibition of multiple P450 1) Increased level of enzymes (3A4.64.46.

19. syndrome18.37.52.123.48. increased sweating Potentially fatal Decreased metabolism of Central serotonin serotonin by MAOIs.45. Increased sedation.48. constipation. seizure risk.112 etc.to 2D6 (weak) and 3A4.50. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments Fluvoxamine (continued) Clozapine Increased level of clozapine213–216 Duloxetine Increased level of duloxetine87 n/a MAOIs Mirtazapine Increased level of mirtazapine218 Clozapine levels can Inhibition of P450 1A2. anticholinergic 51. Somnolence (perhaps). fourfold tein (weak contribution)47.88.217 combined with serotonin reuptake inhibition by fluvoxamine Inhibition of P450 1A2.86 fatigue.284 TABLE A–1. This combination can 2D6.89 syndrome219 levels by as much as fourfold Drug–Drug Interaction Primer . by fluvoxamine34.34. sedation.48. by fluvoxamine Inhibition of P450 1A2 >> 2D6 Dry mouth. 2C9/19.50. and 3A4 by increased risk of serotonin increase mirtazapine fluvoxamine34.124 as well as P-glycoprosymptoms. increase three.

52. ataxia.36.47.112.48.50.220 Mechanisms Clinical consequences Comments Pimozide Phenytoin Increased level of pimozide (probably)217 Increased level of phenytoin221.52. symptoms 63.127 Inhibition of P450 1A2 and Increased EPS and Theoretical concern 3A4 by fluvoxamine45.103–105. 107.52.50.50.47.45.158 tremor.112. nausea. 2D6.155. risk and P-glycoprotein by of EPS fluvoxamine34.208 Tertiary-amine TCAs Typical antipsychotics Increased levels of Inhibition of multiple P450 Increased EPS and other most typical enzymes (1A2.156.48.48.47. thioridazine. dysarthria. 2D6 (weak).224 Inhibition of P450 1A2 Increased sedation and (strong).An Overview of Psychotropic Drug–Drug Interactions TABLE A–1. or pimozide can increase arrhythmogenic potential 285 . Inhibition of multiple P450 Increased arrhythmia risk enzymes and P-glycoprotein and anticholinergic by fluvoxamine34.52.51. and P-glycoprotein by sedation. and 3A4) side effects antipsychotics194.73–77.47.210.48.210 Combining with mesoridazine.117 arrhythmogenic potential Inhibition of both P450 2C9/19 Nystagmus.65.222 Increased levels of tertiary-amine TCAs75. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Olanzapine Pharmacokinetic results Increased level of olanzapine127.48.225 and P-glycoprotein by fluvoxamine34. etc.223. fluvoxamine45.

combined with norepinephrine and dopamine reuptake inhibition by stimulants One case known to the authors Drug–Drug Interaction Primer Potentially fatal . combined with increased serum norepinephrine due to clozapine’s α 2 blockade181.19.227 MAOIs. combined with serotonin.286 TABLE A–1. norepineprine. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug MAOIs All other antidepressants (except for low-dose trazodone)226 Pharmacokinetic results n/a Mechanisms Clinical consequences Comments Potentially fatal Clozapine n/a Stimulants n/a Central serotonin Decreased metabolism of serotonin and norepinephrine syndrome and/or (and sometimes dopamine) by hypertensive crisis18.202.228 Hypertensive crisis18. and dopamine reuptake inhibition by other antidepressants Decreased metabolism of Hypertension norepinephrine by MAOIs.19 Decreased metabolism of norepinephrine and dopamine by MAOIs.

Combination can increased risk of serotonin increase mirtazsyndrome219 apine levels by as much as fourfold Fluvoxamine Inhibition of P450 1A2.197. combined with ziprasidone’s intrinsic serotonergic and noradrenergic reuptake blockade Mirtazapine Carbamazepine Decreased level of mirtazapine230 Increased level of mirtazapine218 Induction of P450 1A2 and 3A4 by carbamazepine88. 2D6.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.137. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Ziprasidone Pharmacokinetic results n/a Mechanisms Clinical consequences Comments Potentially fatal. 50.48.89.89 287 . but a theoretical concern for this combination Central serotonin Decreased metabolism of serotonin and norepinephrine syndrome and/or hypertensive crisis229 by MAOIs.145. 134.146. and 3A4 by fluvoxamine34.198 Possible loss of therapeutic efficacy Somnolence (perhaps).88.

19..100. dysarthria.160. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments Mirtazapine (continued) MAOIs n/a Phenytoin Nefazodone Bupropion Carbamazepine Decreased level of mirtazapine231 Increased levels of mCPP 1) Increased level of carbamazepine and 2) decreased level of nefazodone232 Central serotonin Decreased metabolism of Potentially fatal serotonin and norepinephrine syndrome and/or hypertensive crisis18.135.288 TABLE A–1.198 Acute dysphoric anxiety 1) Ataxia. nausea.200. 197.145.89. diplopia. etc.137.161. sedation. tremor.134. 2) likely loss of therapeutic efficacy Theoretical concern .98 1) Inhibition of P450 3A4 by nefazodone46.198 efficacy Drug–Drug Interaction Primer Inhibition of P450 2D6 by bupropion84. 2) induction of P450 3A4 by carbamazepine97. combined with increased presynaptic release of serotonin and norepinephrine by mirtazapine Induction of P450 3A4 by Possible loss of therapeutic phenytoin88.90 by MAOIs.

98 Induction of P450 3A4 by phenytoin97.117 and 2) P450 2D6 by pimozide97.97.97.233 and 2) mCPP Inhibition of P450 2D6 by Acute dysphoric anxiety fluoxetine plus norfluoxetine34. efficacy but likely 1) Increased risk of QT 1) Potentially fatal and prolongation leading to a 2) theoretical malignant arrhythmia and concern 2) acute dysphoric anxiety 289 . 19. combined with serotonin and norepinephrine crisis18.67.100. 95 reuptake inhibition by nefazodone Inhibition of P450 2D6 by Acute dysphoric anxiety paroxetine34.198 Inhibition of 1) P450 3A4 by nefazodone46.117 Potentially fatal Theoretical concern Likely loss of therapeutic Theoretical concern.98.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.161.98 Central serotonin Decreased metabolism of serotonin and norepinephrine syndrome and/or hypertensive by MAOIs.40. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Fluoxetine Pharmacokinetic results Increased levels of mCPP203 n/a Mechanisms Clinical consequences Comments MAOIs Paroxetine Phenytoin Pimozide Increased levels of mCPP Decreased level of nefazodone Increased levels of 1) pimozide186.

67.53 Comments Theoretical concern MAOIs Potentially fatal Drug–Drug Interaction Primer Nefazodone Phenothiazine antipsychotics Increased levels of mCPP Increased levels of phenothiazine antipsychotics55.54. constipation.107 and P-glycoprotein47.97.103.194 Acute dysphoric anxiety Increased EPS and other side effects Theoretical concern Combining with mesoridazine or thioridazine can increase arrhythmogenic potential .83 Inhibition of P450 2D6 by paroxetine34. fatigue.112 by paroxetine Clinical consequences Increased risk of seizures Dry mouth.67.104. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Paroxetine Bupropion Duloxetine Pharmacokinetic results Increased level of bupropion85 Increased level of duloxetine87 n/a Mechanisms Inhibition of P450 2B6 by paroxetine42. increased sweating Central serotonin syndrome18.86 Decreased metabolism of serotonin by MAOIs.98 Inhibition of P450 2D634. combined with serotonin reuptake inhibition by paroxetine Inhibition of P450 2D6 by paroxetine34.290 TABLE A–1.19.52. sedation.

147. increased prolactin Comments Average increase in the “risperidone active moiety” of roughly 45% TCAs Increased levels of TCAs54.112.134.137. 145.34.47.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1. 2C9.56.208 Clinical consequences EPS.235.67.47.64.36.195.130 Inhibition of P450 2D6 and P-glycoprotein by paroxetine21.57.83 Induction of P450 2B6.197.198 Increased risk of seizures Possible loss of therapeutic efficacy Theoretical concern 291 .148.65.67.75. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Risperidone Pharmacokinetic results Increased level of risperidone234 Mechanisms Inhibition of P450 2D6 > 3A4 and P-glycoprotein by paroxetine34.206. and 3A4 by carbamazepine43.236 Increased arrhythmia risk and anticholinergic symptoms Sertraline Bupropion Carbamazepine Increased level of bupropion85 Decreased level of sertraline237 Inhibition of P450 2B6 by sertraline42.75. 69.70.

62 Drug–Drug Interaction Primer MAOIs n/a Phenytoin Decreased level of sertraline237 Decreased metabolism of serotonin by MAOIs.23. increased risk glucuronosyltransferase of emergence of rash (UGT) 1A4 by sertraline22.238 Possible loss of therapeutic efficacy .150. combined with serotonin reuptake inhibition by sertraline Induction of P450 2B6. 2C9/19. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments Lamotrigine levels typically double with this combination.227.198 Central serotonin syndrome18. Risk of rash and risk of progression to Stevens-Johnson syndrome or toxic epidermal necrolysis exist with this combination.159.19.147. 5′-diphosphate confusion.151 Potentially fatal Sertraline (continued) Lamotrigine Increased level of lamotrigine62 Inhibition of uridine Increased somnolence.57.161. and 3A4 by phenytoin56.292 TABLE A–1.

239 Increased arrhythmia risk Inhibition of multiple P450 and anticholinergic enzymes (mostly 2D6 and symptoms 2C19)21.58–61.47.236.75–77.69.70.240 Mechanisms Clinical consequences Comments TCAs Unclear. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pimozide Pharmacokinetic results Unclear. possible inhibition Increased EPS and of P450 3A4 and 1A2 by arrhythmogenic potential sertraline41.34.208 by sertraline Inhibition of P450 2D6 by bupropion21.195 Increased arrhythmia risk and anticholinergic symptoms TCAs Bupropion Increased levels of TCAs84. possible increased level of pimozide233 Increased levels of TCAs58.44.59–61.195 and P-glycoprotein36.65.64.84.85 293 .64.41.75.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.

148. is 2) inhibition of P450 2C19 reliably decreased by by carbamazepine75.31.78.64.141 carbamazepine.294 TABLE A–1. Carbamazepine’s activity at P450 2C8/ 9 and 2C19 is not yet completely understood. escitalopram Increased levels of secondary-amine TCAs35. P450 2C19 for its metabolism.241.197. Inhibition of P450 2D6 by Increased arrhythmia risk citalopram and by and anticholinergic escitalopram21. also relies strongly on 145.195 while clomipramine is reportedly increased. 2) except for level of clomipramine.149.134. 2C9.195 symptoms Drug–Drug Interaction Primer .146.34. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments TCAs (continued) Carbamazepine 1) Decreased levels of TCAs195. which is reportedly increased142 Citalopram. which carbamazepine43.198.137. Possible loss of therapeutic It is confusing that and 3A4 and UGT1A4 by efficacy amitriptyline.74–76.38 1) Induction of P450 1A2.

195 Clinical consequences Increased arrhythmia risk and anticholinergic symptoms Increased arrhythmia risk and anticholinergic symptoms Comments Fluoxetine Fluvoxamine Increased levels of tertiary-amine TCAs75.52. 60.70.69.116.41.195.43. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Duloxetine Pharmacokinetic results Increased levels of TCAs87 Increased levels of TCAs20.208 by fluoxetine plus norfluoxetine Inhibition of both multiple Increased arrhythmia risk P450 enzymes and and anticholinergic P-glycoprotein by symptoms fluvoxamine34.86.69.208 Haloperidol Increased levels of TCAs Inhibition of P450 2D6 and Increased arrhythmia risk P-glycoprotein by haloperidol and anticholinergic and reduced haloperidol symptoms metabolites21. 115.36.48.73–77.207 Mechanisms Inhibition of P450 2D6 by duloxetine21.44.223.206.64.75.65.52.75.111.46.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.64.70.208 Theoretical concern 295 .40.50.65.224 Inhibition of both multiple P450 enzymes21.34.45.75–77.64.47. 63.195 and P-glycoprotein36.47.36.

70.113.47.110.65. combined with serotonin and norepinephrine reuptake inhibition by TCAs Inhibition of P450 2D6 and Increased arrhythmia risk P-glycoprotein by and anticholinergic paroxetine21. symptoms 75.110.206.183 by MAOIs.70.34.36.36. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments TCAs (continued) MAOIs n/a Paroxetine Increased levels of TCAs54.242 Inhibition of P450 2D6 and P-glycoprotein by phenothiazine antipsychotics21.69. 64.195.69.67.208 (also yielding increased arrhythmogenic potential through pharmacodynamic synergy with mesoridazine and thioridazine) Increased arrhythmia risk and anticholinergic symptoms Combination of TCAs with mesoridazine or thioridazine can increase arrhythmogenic potential .236 Central serotonin Decreased metabolism of Potentially fatal serotonin and norepinephrine syndrome and/or hypertensive crisis18.52.208 Drug–Drug Interaction Primer Phenothiazine antipsychotics Increased levels of TCAs73.75.296 TABLE A–1.111.195.195.19.235.64.

195.195 and P-glycoprotein 36.236.78.34.74–76.75–77. and P-glycoprotein by pimozide.149. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Phenytoin Pharmacokinetic results Decreased levels of TCAs Increased levels of TCAs Mechanisms Induction of P450 2C19 and 3A4 and UGT1A4 by phenytoin74–76.243 Clinical consequences Comments Possible loss of therapeutic Theoretical.159–161.64.198 Inhibition of P450 2D6. but likely efficacy Increased arrhythmogenic Theoretical concern potential Pimozide Sertraline Increased levels of TCAs58.41.47.208 in addition to synergistic QT prolongation233 Inhibition of both multiple P450 enzymes (mostly 2D6 and 2C19)21.64.58–61.70.208 by sertraline Synergistic QT prolongation26.240 Increased arrhythmia risk and anticholinergic symptoms Ziprasidone n/a Increased arrhythmogenic potential 297 .70. 3A4.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1. 80.69.44.36.21.117.69.

189 Note. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Venlafaxine MAOIs Pharmacokinetic results n/a Mechanisms Decreased metabolism of serotonin.298 TABLE A–1.19. TCAs=tricyclic antidepressants. Drug–Drug Interaction Primer . and sometimes dopamine by MAOIs. norepinephrine. Risperidone active moiety is the sum of risperidone and 9-hydroxy-risperidone. norepinephrine. combined with serotonin. and dopamine reuptake inhibition by venlafaxine Clinical consequences Comments Central serotonin Potentially fatal syndrome and/or hypertensive crisis18. MAOIs=monoamine oxidase inhibitors.

137.120–122 Carbamazepine Induction of P450 3A4 by Possible loss of therapeutic carbamazepine118.198 Phenytoin Clozapine Aripiprazole Induction of P450 3A4 by Possible loss of therapeutic Theoretical concern efficacy phenytoin118.120–122 299 .An Overview of Psychotropic Drug–Drug Interactions TABLE A–2. efficacy 145.198 Aripiprazole binds more Possible clinical avidly to the D2 decompensation during receptor than any other antipsychotic crossover titrations antipsychotic118. Significant drug–drug interactions involving antipsychotics Antipsychotic and interacting drugs Aripiprazole All other antipsychotic agents Pharmacokinetic results Mechanisms Significant displacement of other antipsychotics from the dopamine D2 receptor during antipsychotic crossover titrations involving aripiprazole Decreased level of aripiprazole118 Decreased level of aripiprazole Significant displacement of other antipsychotics from the D2 receptor during antipsychotic crossover titrations involving aripiprazole Clinical consequences Comments Aripiprazole binds more Possible clinical avidly to the D2 decompensation during receptor than any other antipsychotic crossover titrations antipsychotic118.161.160.197.134.

2C9.to fourfold 3A4.34.123.44.50. Clozapine levels anticholinergic symptoms. 2D6. 2D6 (weak) and anticholinergic symptoms.51.244. 123–125.300 TABLE A–2.40.48. 124 as well as P-glycoprotein47. roughly 50% with this combination Drug–Drug Interaction Primer .52. 112 by fluvoxamine Possible loss of therapeutic Synergistic risk of blood efficacy dyscrasias (agranulocytosis from clozapine and aplastic anemia from carbamazepine)246 Increased sedation.112 (weak contribution to clozapine bioavailability) by fluoxetine plus norfluoxetine Clozapine levels can Inhibition of P450 1A2.197.198 Clinical consequences Comments Clozapine (continued) Carbamazepine Decreased level of clozapine214. and 3A4.34. 149. Increased sedation.245 Fluoxetine Increased level of clozapine201 Fluvoxamine Increased level of clozapine213–216 Inhibition of P450 1A2.41.148.124 as seizure risk. Significant drug–drug interactions involving antipsychotics (continued) Antipsychotic and interacting drugs Pharmacokinetic results Mechanisms Induction of P450 1A2.43. well as P-glycoprotein (weak contribution)47.46.60. etc.123. 3A4.50. typically increase by seizure risk.146.134. etc. increase three. and UGT1A4 by carbamazepine43.145.137. 2C9/19. 2C9/19.45.

159–161.198 Haloperidol Aripiprazole Significant displacement of other antipsychotics from the D2 receptor during antipsychotic crossover titrations involving aripiprazole Aripiprazole binds more Possible clinical avidly to the D2 decompensation during receptor than any other antipsychotic crossover titrations antipsychotic118. 3A4 and UGT1A4 efficacy by phenytoin50. Significant drug–drug interactions involving antipsychotics (continued) Antipsychotic and interacting drugs MAOIs Pharmacokinetic results Mechanisms n/a Clinical consequences Comments Phenytoin Decreased level of clozapine247 Hypertension One case known to the Decreased metabolism authors of norepinephrine by MAOIs.An Overview of Psychotropic Drug–Drug Interactions TABLE A–2.123–125. 120–122 301 . 149. combined with increased serum norepinephrine due to clozapine’s α2 blockade Induction of P450 2C9/ Possible loss of therapeutic 19.

115 Drug–Drug Interaction Primer Phenytoin Decreased level of haloperidol251 TCAs Increased levels of TCAs Induction of P450 3A4 Possible loss of therapeutic (and possibly pertinent efficacy phase II enzymes) by phenytoin149. Increased EPS and other 3A4.64.195.47. 145.134. 112.111.52. Significant drug–drug interactions involving antipsychotics (continued) Antipsychotic and interacting drugs Pharmacokinetic results Mechanisms Clinical consequences Comments Haloperidol (continued) Carbamazepine Decreased level of haloperidol244.69.149.36.249 Induction of P450 1A2 Possible loss of therapeutic and 3A4 (and possibly efficacy pertinent phase II enzymes) by carbamazepine114.115. 250 Inhibition of P450 1A2.197.52.50.160–162.137.116. and side effects P-glycoprotein by fluvoxamine45.198 Fluvoxamine Increased level of haloperidol210.302 TABLE A–2.248.146.208 .198 Inhibition of P450 2D6 Increased arrhythmia risk Theoretical concern and P-glycoprotein and anticholinergic symptoms by haloperidol and reduced haloperidol metabolites21.114. 70.48.

23.220 Inhibition of P450 1A2 Increased sedation and risk (strong).253 Clinical consequences Comments Aripiprazole binds more Possible clinical avidly to the D2 decompensation during receptor than any other antipsychotic crossover titrations antipsychotic118. 127 Phenytoin Decreased level of olanzapine Induction of UGT1A4 by Possible loss of therapeutic Theoretical concern. 146.112.149 Possible loss of therapeutic efficacy Fluvoxamine Increased level of olanzapine127.149 efficacy but likely 303 .48.52. 2D6 (weak).47. of EPS and P-glycoprotein by fluvoxamine34. phenytoin22.23.An Overview of Psychotropic Drug–Drug Interactions TABLE A–2.120–122 Carbamazepine Induction of P450 1A2 and UGT1A4 by carbamazepine22. Significant drug–drug interactions involving antipsychotics (continued) Antipsychotic and interacting drugs Olanzapine Aripiprazole Pharmacokinetic results Mechanisms Significant displacement of other antipsychotics from the D2 receptor during antipsychotic crossover titrations involving aripiprazole Decreased level of olanzapine252.127.

198 Drug–Drug Interaction Primer Citalopram.146.120–122 Carbamazepine Induction of P450 1A2 Possible loss of therapeutic Theoretical concern and 3A4 by efficacy carbamazepine117.46. escitalopram Fluoxetine n/a Increased level of pimozide (probably) Fluvoxamine Increased level of pimozide (probably) Unclear pharmacodynamic effect Inhibition of P450 1A2 and 3A4 by fluoxetine plus norfluoxetine (probably)41.50. 145.48.134.60 Inhibition of P450 1A2 and 3A4 by fluvoxamine45.137.304 TABLE A–2. Significant drug–drug interactions involving antipsychotics (continued) Antipsychotic and interacting drugs Pimozide Aripiprazole Pharmacokinetic results Mechanisms Significant displacement of other antipsychotics from the D2 receptor during antipsychotic crossover titrations involving aripiprazole Decreased level of pimozide Clinical consequences Comments Aripiprazole binds more Possible clinical avidly to the D2 decompensation during receptor than any other antipsychotic crossover titrations antipsychotic118.197.117 Increase in the QT interval Theoretical concern without an increase in the level of pimozide35.38 Increased EPS and One known case of arrhythmogenic potential serious bradycardia205 Increased EPS and Theoretical concern arrhythmogenic potential .

117.70. possible increased level of pimozide233 Inhibition of 1) P450 3A4 by nefazodone46. 1) Increased risk of QT 2) theoretical concern prolongation leading to a malignant arrhythmia.160. 3A4 and P-glycoprotein by pimozide.117.239 Increased levels of TCAs Inhibition of P450 2D6.80.98.21. Significant drug–drug interactions involving antipsychotics (continued) Antipsychotic and interacting drugs Nefazodone Pharmacokinetic results Mechanisms Increased levels of 1) pimozide186.64.161.208 in addition to synergistic QT prolongation233 n/a Synergistic QT prolongation26 Clinical consequences Comments Phenytoin Sertraline 1) Potentially fatal. 2) P450 2D6 by pimozide97. possible inhibition of P450 3A4 and 1A2 by sertraline41.36.69.59–61. 74–76.100.195.117 Induction of P450 3A4 by phenytoin117.198 Unclear. 2) acute dysphoric anxiety Possible loss of therapeutic Theoretical concern efficacy Increased EPS and arrhythmogenic potential TCAs Increased arrhythmogenic potential Theoretical concern Ziprasidone Increased arrhythmogenic potential Theoretical concern 305 .An Overview of Psychotropic Drug–Drug Interactions TABLE A–2.233 and 2) metachlorophenylpiperazine Decreased level of pimozide Unclear.

306

TABLE A–2. Significant drug–drug interactions involving antipsychotics (continued)
Antipsychotic and interacting drugs Quetiapine Aripiprazole Pharmacokinetic results Mechanisms Significant displacement of other antipsychotics from the D2 receptor during antipsychotic crossover titrations involving aripiprazole 1) Decreased level of quetiapine129,254 and 2) increased level of carbamazepine-10,11epoxide255 Decreased level of quetiapine256 Clinical consequences Comments

Aripiprazole binds more Possible clinical avidly to the D2 decompensation during receptor than any other antipsychotic crossover titrations antipsychotic118,120–122

Carbamazepine

Phenytoin

1) Induction of P450 3A4 by carbamazepine128,129, 134,137,145,197,198; 2) mechanism unknown, but possibly inhibition of epoxide hydrolase Induction of P450 3A4 by phenytoin128,129,160,161,198

1) Possible (or even likely) loss of therapeutic efficacy; 2) possible ataxia, nausea, sedation, confusion, dysarthria, diplopia, tremor, etc. Likely loss of therapeutic Fivefold increase in efficacy the clearance of quetiapine with this combination

Drug–Drug Interaction Primer

An Overview of Psychotropic Drug–Drug Interactions

TABLE A–2. Significant drug–drug interactions involving antipsychotics (continued)
Antipsychotic and interacting drugs Risperidone Aripiprazole Pharmacokinetic results Mechanisms Significant displacement of other antipsychotics from the D2 receptor during antipsychotic crossover titrations involving aripiprazole Decreased level of risperidone257–259 Increased level of risperidone176,234 Clinical consequences Comments

Aripiprazole binds more Possible clinical avidly to the D2 decompensation during receptor than any other antipsychotic crossover titrations antipsychotic118,120–122

Carbamazepine

Induction of P450 3A4 by Possible loss of therapeutic carbamazepine130,134,137, efficacy
145,197,198

Fluoxetine, paroxetine

Inhibition of P450 2D6 > EPS, increased prolactin 3A434,40,46,60,67,130 and P-glycoprotein47,112 by fluoxetine plus norfluoxetine/ paroxetine Induction of P450 3A4 by Possible loss of therapeutic phenytoin130,160,161,198 efficacy

Average increase in the “risperidone active moiety” of roughly 75% when combined with fluoxetine and 45% when combined with paroxetine

Phenytoin

Decreased level of risperidone130

307

308

TABLE A–2. Significant drug–drug interactions involving antipsychotics (continued)
Antipsychotic and interacting drugs Pharmacokinetic results Mechanisms Clinical consequences Comments

Typical antipsychotics (general) Aripiprazole Significant displacement of other antipsychotics from the D2 receptor during antipsychotic crossover titrations involving aripiprazole Increased levels of Bupropion, phenothiazine citalopram, antipsychotics85,87,194 duloxetine, escitalopram, paroxetine

Aripiprazole binds more Possible clinical avidly to the D2 decompensation during receptor than any other antipsychotic crossover titrations antipsychotic118,120–122

Inhibition of P450 2D6 Increased EPS and other side effects by bupropion, paroxetine > citalopram, duloxetine, escitalopram31,34,55,67,84, 86,103,104,107 and P-glycoprotein47,52,112 by paroxetine

Combination of mesoridazine or thioridazine with these agents can increase arrhythmogenic potential (of more theoretical concern with citalopram, duloxetine, escitalopram)

Drug–Drug Interaction Primer

An Overview of Psychotropic Drug–Drug Interactions

TABLE A–2. Significant drug–drug interactions involving antipsychotics (continued)
Antipsychotic and interacting drugs Carbamazepine Pharmacokinetic results Mechanisms Decreased levels of typical Induction of P450 1A2, antipsychotics244 3A4, and UGT1A4 by carbamazepine23,79,103,
107,108,114,117,134,137,145, 146,149,197,198,210

Clinical consequences Possible loss of therapeutic efficacy

Comments

Citalopram, escitalopram

Increased levels of phenothiazine antipsychotics85,87,194

Increased EPS and other See information for side effects interaction of typical antipsychotics with bupropion, citalopram, duloxetine, escitalopram, paroxetine Increased EPS and other See information for side effects interaction of typical antipsychotics with bupropion, citalopram, duloxetine, escitalopram, paroxetine

Duloxetine

Increased levels of phenothiazine antipsychotics85,87,194

See information for interaction of typical antipsychotics with bupropion, citalopram, duloxetine, escitalopram, paroxetine See information for interaction of typical antipsychotics with bupropion, citalopram, duloxetine, escitalopram, paroxetine

309

310

TABLE A–2. Significant drug–drug interactions involving antipsychotics (continued)
Antipsychotic and interacting drugs Pharmacokinetic results Mechanisms Clinical consequences Comments Combination of mesoridazine or thioridazine with fluoxetine can increase arrhythmogenic potential Combination of mesoridazine, thioridazine, or pimozide with fluvoxamine can increase arrhythmogenic potential See information for interaction with bupropion, citalopram, duloxetine, escitalopram, paroxetine

Typical antipsychotics (general) (continued) Increased EPS and other Fluoxetine Increased levels of most Inhibition of multiple side effects P450 enzymes (1A2, typical 2D6, and 3A4)34,40,41, antipsychotics194,209 46,60,103–105,107,210 and P-glycoprotein47,52,112 by fluoxetine plus norfluoxetine Fluvoxamine Increased levels of Inhibition of multiple Increased EPS and other most typical P450 enzymes (1A2, side effects antipsychotics194,210,225 2D6, and 3A4) and P-glycoprotein by fluvoxamine34,47,48,50,52,
103–105,107,112,210

Drug–Drug Interaction Primer

Paroxetine

Increased levels of phenothiazine antipsychotics85,87,194

Increased EPS and other See information for side effects interaction of typical antipsychotics with bupropion, citalopram, duloxetine, escitalopram, paroxetine

An Overview of Psychotropic Drug–Drug Interactions

TABLE A–2. Significant drug–drug interactions involving antipsychotics (continued)
Antipsychotic and interacting drugs Phenytoin Pharmacokinetic results Mechanisms Decreased levels of typical Induction of P450 3A4 antipsychotics251 and UGT1A4 by phenytoin79,106,109,149,
160,161,198

Clinical consequences Possible loss of therapeutic efficacy

Comments

TCAs

Increased levels of TCAs73,110,195,242

Ziprasidone

n/a

Inhibition of P450 2D6 Increased arrhythmia risk and anticholinergic and P-glycoprotein by symptoms phenothiazine antipsychotics21,36,52,64,69,70, 110,111,113,195,208 (also yielding increased arrhythmogenic potential through pharmacodynamic synergy in combination of TCAs with mesoridazine or thioridazine) Synergistic QT Increased arrhythmogenic prolongation with potential chlorpromazine, mesoridazine, pimozide, or thioridazine26

Combination of mesoridazine or thioridazine with TCAs can increase arrhythmogenic potential

Theoretical concern

311

312

TABLE A–2. Significant drug–drug interactions involving antipsychotics (continued)
Antipsychotic and interacting drugs Ziprasidone Aripiprazole Pharmacokinetic results Mechanisms Significant displacement of other antipsychotics from the D2 receptor during antipsychotic crossover titrations involving aripiprazole Decreased level of ziprasidone134 n/a Clinical consequences Comments

Aripiprazole binds more Possible clinical avidly to the D2 decompensation during receptor than any other antipsychotic crossover titrations antipsychotic118,120–122

Carbamazepine

Induction of P450 3A4 by Possible loss of therapeutic carbamazepine26,134,137, efficacy
145,197,198

MAOIs

Phenytoin

Decreased level of ziprasidone

Decreased metabolism of Central serotonin syndrome Potentially fatal, but a and/or hypertensive theoretical concern for serotonin and crisis229 this combination norepinephrine by MAOIs, combined with ziprasidone’s intrinsic serotonergic and noradrenergic reuptake blockade Induction of P450 3A4 by Possible loss of therapeutic Theoretical concern phenytoin26,134,160,161,198 efficacy

Drug–Drug Interaction Primer

An Overview of Psychotropic Drug–Drug Interactions

TABLE A–2. Significant drug–drug interactions involving antipsychotics (continued)
Antipsychotic and interacting drugs Pimozide TCAs Typical antipsychotics Pharmacokinetic results Mechanisms n/a n/a n/a Synergistic QT prolongation26 Synergistic QT prolongation26,243 Synergistic QT prolongation with chlorpromazine, mesoridazine, or thioridazine26 Clinical consequences Increased arrhythmogenic potential Increased arrhythmogenic potential Increased arrhythmogenic potential Comments Theoretical concern Theoretical concern Theoretical concern

Note. Risperidone active moiety is the sum of risperidone and 9-hydroxy-risperidone. EPS= extrapyramidal symptoms; MAOIs=monoamine oxidase inhibitors; TCAs= tricyclic antidepressants; UGT=uridine 5′-diphosphate glucuronosyltransferase.

313

50.33.146.198 Induction of P450 2B6 by Possible loss of therapeutic carbamazepine83. efficacy 145.197.145.134.146 Possible loss of therapeutic efficacy Synergistic risk of blood dyscrasias (agranulocytosis from clozapine and aplastic anemia from carbamazepine)246 Theoretical concern Drug–Drug Interaction Primer . escitalopram Clozapine Decreased level of bupropion192.147 efficacy Induction of P450 3A4 by Possible loss of therapeutic carbamazepine32.245 Mechanisms Clinical consequences Comments Induction of P450 3A4 by Possible loss of therapeutic carbamazepine118.244.137. 134.137.123–125.148. Possible loss of therapeutic 3A4. 2C9.137.37.314 TABLE A–3.134. Significant drug–drug interactions involving mood stabilizers Mood stabilizer and interacting Pharmacokinetic drug results Carbamazepine Aripiprazole Decreased level of aripiprazole118 Bupropion Citalopram.197.193 Decreased levels of citalopram and escitalopram196 Decreased level of clozapine214.149.198 Induction of P450 1A2. efficacy 197. and UGT1A4 by efficacy carbamazepine43.198 Duloxetine Decreased level of duloxetine Induction of P450 1A2 by carbamazepine37.145.

200 and P-glycoprotein47. nausea. theoretical concern Haloperidol.249 Possible loss of therapeutic efficacy 315 .145. 2C9)42.248.134. 2B6. diplopia. 2B6.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3.200 and P-glycoprotein 47. Comments Fluvoxamine 1) Increased level of carbamazepine211.60.135.244. The decrease in dysarthria.43. 2C9)41–43. etc.137.146 Induction of P450 1A2 and 3A4 by carbamazepine88.135.138 by fluoxetine plus norfluoxetine 1) Inhibition of multiple P450 enzymes (3A4. sedation.89.52. fluvoxamine levels is a etc.46.51. tremor.198 Clinical consequences Ataxia.212 and 2) decreased level of fluvoxamine Ataxia. 114. dysarthria.50. nausea.149.48.138 by fluvoxamine. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Fluoxetine Increased level of carbamazepine199 Mechanisms Inhibition of both multiple P450 enzymes (3A4.45.146. sedation. tremor. diplopia.197. mirtazapine Decreased level of haloperidol or mirtazapine230. 1A2. 1A2. 2) induction of P450 1A2 by carbamazepine48.

23. etc. dysarthria. 145.316 TABLE A–3. diplopia. sedation.137.197. dysarthria.244. one study suggested this increase occurs. Drug–Drug Interaction Primer Mirtazapine Nefazodone Decreased level of See information for haloperidol or interaction of mirtazapine230.. diplopia.248. 10. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Mechanisms Clinical consequences Comments The increase in carbamazepine10. nausea.11-epoxide with this combination is controversial.11-epoxide260 confusion.200. mirtazapine 1) Increased level of 1) Inhibition of P450 3A4 carbamazepine and by nefazodone46. tremor. level of carbamazepinenausea.149. 2) likely loss of therapeutic efficacy . therapeutic efficacy. etc. 2) decreased level of 2) induction of P450 3A4 nefazodone232 by carbamazepine97.149 and carbamazepine22. 2) possible increase in 2) mechanism unknown 2) possible ataxia.198 Possible loss of therapeutic efficacy 1) Ataxia.100.135. and others suggested no such increase260–263 Carbamazepine (continued) Lamotrigine 1) Decreased level of 1) Induction of UGT1A4 by 1) Possible loss of lamotrigine137. sedation.134.249 carbamazepine with haloperidol. tremor.

An Overview of Psychotropic Drug–Drug Interactions TABLE A–3. carbamazepine and phenytoin package inserts mention possible decreases due to induction. 1) Possible loss of 2C9.156 Although evidence supports the increase in phenytoin levels in this combination. 2) possible nystagmus.143 and 2) reported increased level of phenytoin141. 2) inhibition of ataxia. and 3A4 by therapeutic efficacy. 317 . P450 2C19 by carbamazepine68.200 .127.23. sedation. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Olanzapine Decreased level of olanzapine252. tremor. phenytoin135.143 Mechanisms Clinical consequences Comments Phenytoin Induction of P450 1A2 and Possible loss of therapeutic UGT1A4 by efficacy carbamazepine22. 198.159–161. It is unclear how carbamazepine’s 2C19 inhibition could overcome its 2C9 induction to produce elevated phenytoin levels.147.141.146.253 1) Decreased level of carbamazepine137.149 1) Induction of P450 2B6. nausea. etc. dysarthria.

tremor.11epoxide255 Decreased level of risperidone257–259 Decreased level of sertraline237 Mechanisms Induction of P450 1A2 and 3A4 by carbamazepine117. 2) mechanism 2) possible ataxia. hydrolase) Induction of P450 3A4 by Possible loss of therapeutic carbamazepine130.137.137.197. 145.134. nausea.129. 254 and 2) increased level of carbamazepine-10.146.137. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Carbamazepine (continued) Pimozide Decreased level of pimozide Quetiapine 1) Decreased level of quetiapine129. inhibition of epoxide etc.57. unknown (possibly dysarthria.134.137.145.197.198 Drug–Drug Interaction Primer Sertraline Induction of P450 2B6.198 .197.147.134. efficacy 197.145.148. diplopia. confusion. 134.198 Clinical consequences Possible loss of therapeutic efficacy Comments Theoretical concern Risperidone 1) Induction of P450 3A4 by 1) Possible (or even likely) loss of therapeutic efficacy.56.198 . 145.318 TABLE A–3. sedation. carbamazepine128. 2C9. Possible loss of therapeutic and 3A4 by efficacy carbamazepine43.

141 Topiramate 1) Decreased level of 1) Induction of phase II topiramate163.197.146.163.167. which is reportedly increased142 198.265. should be reliably decreased by carbamazepine195 and that the level of clomipramine is reportedly increased.78. which relies strongly on P450 2C19 for its metabolism.134. for the level of 74–76.241 2) except 2C9.195. and 3A4 and UGT1A4 efficacy (TCAs) by carbamazepine37. Carbamazepine’s activity at P450 2C8/9 and 2C19 is not yet completely understood.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3.149. 2) induction (mild) of P450 3A4 by topiramate135.137. 2) inhibition of P450 2C19 by carbamazepine75.200 Possible loss of therapeutic efficacy 319 .264 and metabolism by carbamaze2) possible decreased pine (possibly at UGT level of carbamazepine 1A4)149.148. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Mechanisms Clinical consequences Comments It is confusing that the level of amitriptyline. clomipramine.168.164.43. Result #2 is a theoretical concern Tricyclic 1) Decreased levels of 1) Induction of P450 1A2. Possible loss of therapeutic antidepressants TCAs.145.

172.107. diplopia.197.137.170 3) inhibition of dysarthria. sedation. of the hepatotoxic 2) induction of P450 2C9 4-ene-valproate (likely) by carbamazepine.268 epoxide137 Decreased level of Induction of P450 3A4 by Possible loss of therapeutic ziprasidone134 carbamazepine26. 148.114.267 and etc.175.137.198 Drug–Drug Interaction Primer .146. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Carbamazepine (continued) Typical Decreased levels of antipsychotics typical (general) antipsychotics244 Mechanisms Clinical consequences Comments Induction of P450 1A2.103.320 TABLE A–3. 3) increased level of epoxide hydrolase by carbamazepine-10. confusion. 198. Possible loss of therapeutic and UGT1A4 by efficacy carbamazepine23. 108.149. 3A4. metabolite. 3) possible ataxia.171 hepatitis.117.134. efficacy 197.11valproate137.174. tremor.79.145.134.145.210 Valproate Ziprasidone 1) Decreased level of 1) Induction of phase II 1) Possible loss of therapeutic valproate.43. 2) transaminase elevations or even frank 2) increased production carbamazepine. nausea.149.172.266 metabolism by efficacy.

Risk of rash lamotrigine62 risk of emergence of rash and progression to Stevens-Johnson syndrome or toxic epidermal necrolysis exist with this combination.269 efficacy lamotrigine149.150.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3.23.11-epoxide is level of carbamazepinedysarthria.151 321 .62 confusion. Lamotrigine level can Sertraline Increased level of sertraline22. occurs. one study suggested it 10. 10. 2) possible ataxia.149 and efficacy.23. confusion.23. and increased double. tremor. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Mechanisms Clinical consequences Comments Lamotrigine Carbamazepine 1) Decreased level of 1) Induction of UGT1A4 by 1) Possible loss of therapeutic The increase in lamotrigine137. diplopia.11-epoxide260 etc. and others suggested no such increase260–263 Oxcarbazepine Decreased level of Induction of UGT1A4 by Possible loss of therapeutic lamotrigine154 oxcarbazepine22.154 efficacy Induction of UGT1A4 by Possible loss of therapeutic Phenytoin Decreased level of phenytoin149. carbamazepinecarbamazepine22.149. controversial.269 Inhibition of UGT1A4 by Increased somnolence. sedation. 2) possible increase in 2) mechanism unknown nausea.

162 Possible loss of therapeutic efficacy 1) Nystagmus. 154 1) Inhibition of P450 2C19 by oxcarbazepine141. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Lamotrigine (continued) Valproate 1) Increased level of lamotrigine149. ataxia. 2) theoretical concern Drug–Drug Interaction Primer Oxcarbazepine Lamotrigine Decreased level of lamotrigine154 Phenytoin 1) Increased level of phenytoin141 and 2) decreased level of oxcarbazepine269. 2) induction of phase II metabolism by phenytoin149. 2) likely mild phase II induction by lamotrigine151.269.154.. 23.171 Clinical consequences 1) Increased somnolence.268. etc. Risk of rash and risk of progression to Stevens-Johnson syndrome or toxic epidermal necrolysis exist with this combination150. 2) possible loss of therapeutic efficacy .270 Induction of UGT1A4 by oxcarbazepine22.151.154. sedation. nausea.322 TABLE A–3.269 and 2) mild (about 25%) decrease in valproate levels151 Mechanisms 1) Inhibition of UGT1A4 by valproate149. dysarthria. tremor. and increased risk of emergence of rash. confusion. 2) possible loss of therapeutic efficacy Comments 1) Lamotrigine level typically doubles with this combination.

Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Topiramate Phenytoin Aripiprazole Decreased level of topiramate265 Mechanisms Clinical consequences Comments Induction of phase II metab.200. and 3A4 by efficacy. 1) Possible loss of therapeutic Some evidence supports 2C9.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3.198 efficacy Possible loss of therapeutic Theoretical concern. 2) possible the increase in phenyphenytoin135. nystagmus. Induction of P450 2B6 by efficacy but likely phenytoin83.161. tremor.147 1) Induction of P450 2B6. Decreased level of aripiprazole Bupropion Decreased level of bupropion Carbamazepine 1) Decreased level of carbamazepine137.159161. etc.147.141.156 insert notes possible decreases in phenytoin levels due to induction. toin levels with this combination.Possible loss of therapeutic olism by oxcarbazepine154 efficacy Induction of P450 3A4 by Possible loss of therapeutic Theoretical concern phenytoin118. It is unclear how carbamazepine’s 2C19 inhibition could overcome its 2C9 induction to produce elevated phenytoin levels. ataxia.143 and 2) reported increased level of phenytoin141.198. carbamazepine package by carbamazepine68. dysarthria. nausea. yet the 2) inhibition of P450 2C19 sedation.160.143 323 .

ataxia.33. tremor. tremor. fluvoxamine Nystagmus.155.156 and P-glycoprotein47. etc. sedation. dysarthria.44. nausea. . 221. 159–161. and UGT1A4 by phenytoin50. sedation.68.123–125. nausea.149. Decreased levels of escitalopram citalopram and escitalopram Clozapine Decreased level of clozapine247 Mechanisms Induction of P450 3A4 and 2C19 by phenytoin32. 222 Inhibition of both P450 2C9/1943.222 Fluvoxamine Increased level of phenytoin204.324 TABLE A–3. ataxia.198 Fluoxetine. Drug–Drug Interaction Primer Nystagmus.51.198 Clinical consequences Possible loss of therapeutic efficacy Possible loss of therapeutic efficacy Comments Theoretical concern Induction of P450 2C9/19. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Phenytoin (continued) Citalopram. dysarthria. 159–161.221.158 by fluoxetine plus norfluoxetine and by fluvoxamine45.48. 3A4. etc.52 See information for interaction of phenytoin with fluoxetine. fluvoxamine Increased level of phenytoin204.

198 Induction of UGT1A4 by phenytoin22. mirtazapine Induction of P450 3A4 by phenytoin97.149. efficacy but likely Possible loss of therapeutic Theoretical concern.149 1) Inhibition of P450 2C19 by oxcarbazepine68.161.269 See information for interaction of phenytoin with haloperidol.270 Mechanisms Induction of P450 3A4 (and possibly pertinent phase II enzymes) by phenytoin88.162 Clinical consequences Possible loss of therapeutic efficacy Comments Lamotrigine Mirtazapine Possible loss of therapeutic efficacy Possible loss of therapeutic efficacy Nefazodone Olanzapine Oxcarbazepine Likely loss of therapeutic Theoretical concern.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3. dysarthria. 2) possible loss of therapeutic efficacy 325 . 2) induction of phase II metabolism by phenytoin149.251 Decreased level of nefazodone Decreased level of olanzapine 1) Increased level of phenytoin141 and 2) decreased level of oxcarbazepine269. nausea.198 Induction of UGT1A4 by phenytoin149.160–162. efficacy but likely 1) Nystagmus.251 Decreased level of lamotrigine149. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Haloperidol..156.141.89. sedation.269 Decreased level of haloperidol or mirtazapine231. ataxia. mirtazapine Decreased level of haloperidol or mirtazapine231. etc.23. tremor.

326 TABLE A–3.198 Theoretical concern. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Phenytoin (continued) Pimozide Decreased level of pimozide Quetiapine Decreased level of quetiapine256 Mechanisms Induction of P450 3A4 by phenytoin117.160.149.159. Possible loss of therapeutic 2C9/19.57. and 3A4 by efficacy phenytoin56.147.198 Induction of P450 3A4 by phenytoin128.78.161.198 efficacy Induction of P450 2B6.129.160.161.160.198 Induction of P450 2C19 and Possible loss of therapeutic efficacy 3A4 and UGT1A4 by phenytoin74–76.161. but likely .161. 159–161.198 Clinical consequences Possible loss of therapeutic efficacy Likely loss of therapeutic efficacy Comments Theoretical concern This combination produces a fivefold increase in the clearance of quetiapine Drug–Drug Interaction Primer Risperidone Sertraline Decreased level of risperidone130 Decreased level of sertraline237 Decreased levels of TCAs TCAs Induction of P450 3A4 by Possible loss of therapeutic phenytoin130.

160.171.156. valproate172.268.272 by of therapeutic efficacy.155.149. the patient’s free of phenytoin. checked.159.167..162. and necessary to check a free valproate level 3) increased production 3) induction of P450 2C9 when valproate is of the hepatotoxic (likely) by phenytoin159.. 2) possible loss phenytoin level (as opposed to a total increase in the free sites.273. nausea.264.198 Clinical consequences 1) Nystagmus.272. level) should be fraction of 3) transaminase elevations valproate148. ataxia. 2) induction of phase II metabolism by phenytoin149. disproportionate from plasma protein binding tremor. 265. tremor.166. 2) possible loss of therapeutic efficacy Possible loss of therapeutic efficacy Comments Typical Decreased levels of antipsychotics typical (general) antipsychotics251 Valproate 1) Increased ‘‘total’’ levels 1) Inhibition of P450 2C9.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3. ataxia. sedation.106.170.170 combined with 4-ene-valproate phenytoin metabolite172. dysarthria. With this combination.109. 161. nausea.271 Mechanisms 1) Inhibition of P450 2C19 by topiramate68.162–164 Induction of P450 3A4 and UGT1A4 by phenytoin79. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Topiramate 1) Increased level of phenytoin271 and 2) decreased level of topiramate163.273 It is phenytoin175.173 1) Nystagmus. etc.267 327 . etc.156. with a combined with displacement sedation. 2) induction of P450 2C9/19 or even frank hepatitis and phase II metabolism by 2) decreased level of generally not phenytoin149. dysarthria.

Phenytoin 1) Increased level of by topiramate68.163..134.164.264 and efficacy theoretical concern metabolism by 2) possible decreased carbamazepine (possibly at level of carbamazepine UGT1A4)149.167. 2) induction (mild) of P450 3A4 by topiramate135. sedation.160.328 TABLE A–3.156. phenytoin271 and tremor.162–164 Drug–Drug Interaction Primer .265.161. ataxia.271 phenytoin149. etc.268. metabolism by 265.198 Clinical consequences Possible loss of therapeutic efficacy Comments Theoretical concern Topiramate Carbamazepine 1) Decreased level of Possible loss of therapeutic Result #2 is a 1) Induction of phase II topiramate163. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Phenytoin (continued) Ziprasidone Decreased level of ziprasidone Mechanisms Induction of P450 3A4 by phenytoin26.200 Oxcarbazepine Decreased level of Induction of phase II Possible loss of therapeutic topiramate265 metabolism by efficacy oxcarbazepine154 1) Inhibition of P450 2C19 1) Nystagmus.168.166. nausea.264.167. 2) possible loss 2) decreased level of 2) induction of phase II of therapeutic efficacy topiramate163. dysarthria.

3) possible ataxia.171 Stevens-Johnson syndrome or toxic epidermal necrolysis exist with this combination150. diplopia. 4-ene-valproate (likely) by dysarthria. etc.148. metabolite172. 269 valproate149.175. 3) increased level of 3) inhibition of epoxide carbamazepine-10. tremor. Risk of and 2) mild (about 2) likely mild phase II rash and risk of 2) possible loss of 25%) decrease in induction by therapeutic efficacy progression to valproate levels151 lamotrigine151. sedation. and increased typically doubles in risk of emergence of rash.268.151. combination. 2) transaminase elevations or even frank 2) increased production carbamazepine149.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3. hepatitis.174. 2) theoretical concern 329 .267. and carbamazepine43. confusion.268 epoxide137 Lamotrigine 1) Increased level of 1) Inhibition of UGT1A4 by 1) Increased somnolence.171.266.11hydrolase by valproate137. 154. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Mechanisms Clinical consequences Comments Valproate Carbamazepine 1) Decreased level of 1) Induction of phase II 1) Possible loss of therapeutic valproate172. metabolism by efficacy.154.149. of the hepatotoxic 2) induction of P450 2C9 nausea. confusion.269.170. 1) Lamotrigine level lamotrigine.

162. Drug–Drug Interaction Primer . checked. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Mechanisms Clinical consequences Comments Valproate (continued) Phenytoin 1) Increased ‘‘total’’ levels 1) Inhibition of P450 2C9. valproate172.330 TABLE A–3.156. with a combined with displacement sedation.171.170. ataxia. the patient’s free of phenytoin.273.273 It is phenytoin175. etc. and necessary to check a free valproate level 3) increased production 3) induction of P450 2C9 when valproate is of the hepatotoxic (likely) by phenytoin159. 2) induction of P450 2C9/19 or even frank hepatitis and phase II metabolism by 2) decreased level of generally not phenytoin149.267 Note.155. nausea.. disproportionate from plasma protein binding tremor.272 by of therapeutic efficacy. With this combination.173 1) Nystagmus. level) should be fraction of 3) transaminase elevations valproate148. dysarthria.170 combined with 4-ene-valproate phenytoin metabolite172. 2) possible loss phenytoin level (as opposed to a total increase in the free sites. UGT= uridine 5′-diphosphate glucuronosyltransferase.272.159.

277 Increased level of alprazolam96. efficacy alprazolam145 197.274 Clarithromycin. fluvoxamine Nefazodone Phenytoin St.274–276 Inhibition of P450 3A4 by fluoxetine and by fluvoxamine45. John’s wort274.An Overview of Psychotropic Drug–Drug Interactions TABLE A–4. John’s wort Increased level of alprazolam274 Increased level of alprazolam217.137.274 Inhibition of P450 3A4 by nefazodone46.46.161.145.186.274 Induction of P450 3A4 by phenytoin 160.278–280 Increased somnolence Increased somnolence Increased somnolence Possible loss of therapeutic efficacy Possible loss of therapeutic efficacy Theoretical concern 331 .100 Decreased level of alprazolam Decreased level of alprazolam278.279 Inhibition of P450 3A4 by clarithromycin and by erythromycin 186. erythromycin Fluoxetine.274 Induction of P450 3A4 by St.50.100. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents Index drug and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments Alprazolam (metabolized by P450 3A4) Induction of P450 3A4 by Possible loss of therapeutic Carbamazepine Decreased level of carbamazepine134.

efficacy 197.282. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug Aspirin Valproate Pharmacokinetic results Increased level of ‘‘free’’ or unbound valproate29. juice186.282 Inhibition of P450 3A4 Increased somnolence. etc.281 Mechanisms Clinical consequences Comments The patient’s free valproate level (versus a total level) should be checked when valproate is combined with even moderate doses of aspirin (325 mg/day or more) Plasma protein binding Somnolence.275. clarithromycin and by headache.286 . nausea.282 Theoretical concern283 Inhibition of P450 3A4 by Increased somnolence. confusion. nausea.276.182 Buspirone (metabolized by P450 3A4) Carbamazepine Decreased level of buspirone282 Clarithromycin.137.332 TABLE A–4. displacement of valproate incoordination. erythromycin 186.145.30. nausea. etc. β-oxidation by aspirin29.275. erythromycin Grapefruit juice Increased level of buspirone275. etc.275. and inhibition of vomiting.172. 284 Increased level of buspirone285 Drug–Drug Interaction Primer Induction of P450 3A4 by Possible loss of therapeutic carbamazepine134. (in the gut) by grapefruit headache.30.285.

can be important for individual patients Caffeine (metabolized by P450 1A2) Clozapine Increased level of clozapine287–289 Inhibition of P450 1A2 by caffeine50. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug Pharmacokinetic results Mechanisms Decreased metabolism of serotonin combined with partial serotonin agonism by buspirone Inhibition of P450 3A4 by nefazodone46. Possible loss of therapeutic efficacy Possible loss of therapeutic efficacy Comments Monoamine oxidase n/a inhibitors (MAOIs) Nefazodone Phenytoin St.289.282 Induction of P450 3A4 by phenytoin 160.282 Induction of P450 3A4 by St.An Overview of Psychotropic Drug–Drug Interactions TABLE A–4.19. central serotonin syndrome has been reported with this combination278 Although this combination typically raises clozapine levels only about 25%. constipation.275.100.275. this effect.186.123.278–280 Clinical consequences Central serotonin syndrome and/or hypertensive crisis18.290 Sedation. blurry vision. headache.161. etc. John’s wort275. and/or its discontinuation. John’s wort Increased level of buspirone282 Decreased level of buspirone282 Decreased level of buspirone Theoretical concern283 Theoretical concern.282 Increased somnolence. nausea. 333 . hypersalivation. etc.

295 Drug–Drug Interaction Primer Lamotrigine Decreased level of lamotrigine296. Increased renal excretion Possible loss of therapeutic Lithium Decreased level of of lithium caused by efficacy lithium291. ethinylestradiol197. anxiety.145. excessive caffeine48 diuresis.299 Induction of P450 3A4 by Unintended pregnancy. 290 tachycardia.298. etc. breakthrough bleeding.334 TABLE A–4.23. Fluvoxamine Increased level of fluvoxamine48. . 294 197. Carbamazepine Decreased level of carbamazepine134.297 Induction of UGT1A4 by Possible loss of therapeutic ethinylestradiol22. etc.292 caffeine293 Ethinylestradiol (metabolized by P450 3A4) Induction of P450 3A4 by Unintended pregnancy. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments Caffeine (metabolized by P450 1A2) (continued) Inhibition of P450 1A2 by Agitation. 289. etc. 294.297 efficacy This combination typically produces a 50% decrease in lamotrigine levels Oxcarbazepine Decreased level of ethinylestradiol153.137.296. oxcarbazepine153.295 breakthrough bleeding.

etc. sedation.161.An Overview of Psychotropic Drug–Drug Interactions TABLE A–4. topiramate168.299 Grapefruit juice Buspirone Increased level of buspirone285 Increased level of carbamazepine301 Carbamazepine Inhibition of P450 3A4 (in Increased somnolence. St. 294 Mechanisms Clinical consequences Comments Induction of P450 3A4 by Unintended pregnancy. diplopia. nausea. juice186.275. nausea. 286. (in the gut) > 1A2 and dysarthria.285. 280. the gut) by grapefruit headache. etc. P-glycoprotein by tremor.138.300 Topiramate Decreased level of ethinylestradiol169.286 Inhibition of P450 3A4 Ataxia.285. 294. Induction of P450 3A4 by Unintended pregnancy.295 breakthrough bleeding.295 breakthrough bleeding. etc. John’s wort Decreased level of ethinylestradiol278.295 breakthrough bleeding. etc. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug Phenytoin Pharmacokinetic results Decreased level of ethinylestradiol197. grapefruit juice135. etc. St. phenytoin 160. John’s wort278–280. Induction of P450 3A4 by Unintended pregnancy.302–304 335 .

nefazodone Increased ‘‘statin’’ blood level286.) with grapefruit juice.303.285. 307–309 Nefazodone Increased ‘‘statin’’ blood level286.305.336 TABLE A–4. lovastatin. etc. 307–309 Inhibition of P450 3A4 Increased risk of (in the gut) by grapefruit rhabdomyolysis and juice or nefazodone46.145.) See information for Increased risk of rhabdomyolysis and interaction of HMGCoA reductase inhibitors associated symptoms (fatigue.286.305.306 Drug–Drug Interaction Primer Grapefruit juice.286.306 (fatigue. nefazodone . myalgias.137. myalgias.100.305. and simvastatin (metabolized by P450 3A4) Induction of P450 3A4 by Possible loss of therapeutic Carbamazepine Decreased ‘‘statin’’ carbamazepine134. efficacy blood level144 197. associated symptoms 186. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments Theoretical concern186.305. arrhythmogenic potential 304 Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (‘‘statins’’). etc.233 Grapefruit juice (continued) Pimozide Increased level of pimozide Inhibition of P450 3A4 Increased extrapyramidal (in the gut) > 1A2 by symptoms and grapefruit juice285. specifically atorvastatin.

monitoring of lithium level is advised 337 .306 Lithium Increased lithium AngiotensinDecreased renal excretion Dizziness. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug Phenytoin St. vomiting. efficacy John’s wort278–280.161. nausea.305. converting enzyme level28. blurry vision. (ACE) inhibitors inhibitors and confusion.311–313 of lithium caused by ACE tremor. etc. John’s wort Pharmacokinetic results Decreased ‘‘statin’’ blood level306 Decreased ‘‘statin’’ blood level280. and angiotensin II angiotensin II receptor receptor antagonists antagonists Loop diuretics Variable or no change Unclear Unclear in lithium levels27 This effect is unpredictable.305.306 efficacy Induction of P450 3A4 and Possible loss of therapeutic P-glycoprotein by St.310 Mechanisms Clinical consequences Comments Induction of P450 3A4 by Possible loss of therapeutic phenytoin 160.An Overview of Psychotropic Drug–Drug Interactions TABLE A–4.

blurry vision. except aspirin and sulindac Decreased renal excretion Dizziness.292 Thiazide and Increased lithium potassium-sparing level27. etc. Close monitoring of lithium level is advised Lithium (continued) Nonsteroidal anti. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments This effect can be quite variable in magnitude.291. nausea. of lithium caused by tremor. nausea. NSAIDs confusion. vomiting. Osmotic diuretics and xanthines Decreased level of lithium28. except amiloride316 Drug–Drug Interaction Primer .314 drugs (NSAIDs). of lithium caused by tremor. blurry vision.338 TABLE A–4.315 Decreased renal excretion Dizziness.Increased lithium inflammatory level28.28 diuretics. except amiloride Increased renal excretion Possible loss of therapeutic of lithium caused by efficacy osmotic diuretics and xanthines293. vomiting. thiazide and potassiumconfusion. etc. from minimal changes to doubling or even greater changes in lithium levels. sparing diuretics.

279 Decreased level of buspirone Mechanisms Clinical consequences Comments Induction of P450 3A4 by Possible loss of therapeutic St. etc.278–280 efficacy Induction of P450 3A4 by Possible loss of therapeutic efficacy St.306 HMG-CoA reductase inhibitors (‘‘statins’’). 280. central serotonin syndrome has been reported with this combination278 Ethinylestradiol Decreased level of ethinylestradiol278. John’s wort274.300 Induction of P450 3A4 by Unintended pregnancy. and simvastatin Decreased ‘‘statin’’ blood level280.An Overview of Psychotropic Drug–Drug Interactions TABLE A–4.278–280 Theoretical concern. specifically atorvastatin. efficacy John’s wort278–280.305. St. Induction of P450 3A4 and Possible loss of therapeutic P-glycoprotein by St. John’s wort275. John’s wort278–280 breakthrough bleeding. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug St. John’s wort Alprazolam Buspirone Pharmacokinetic results Decreased level of alprazolam278.310 339 . lovastatin.

John’s wort with syndrome278.317 serotonergically active antidepressants are of theoretical concern. John’s wort Synergistic serotonin Increased risk of central All combinations of reuptake inhibition serotonin St. although the same could be said of pharmacokinetically safe combinations of SSRIs with other serotonergically active antidepressants (such as sertraline plus mirtazapine) Drug–Drug Interaction Primer . John’s wort (continued) MAOIs n/a Selective serotonin n/a reuptake inhibitors (SSRIs) Decreased metabolism of Increased risk of central Theoretical concern serotonin by MAOIs.280.317 combined with serotonin reuptake inhibition by St.19. serotonin syndrome18.340 TABLE A–4. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments St.

49.322 efficacy Induction of P450 1A2 by Possible loss of therapeutic Fluvoxamine Decreased level of tobacco smoking48.322 341 .318 Induction of P450 1A2 by Possible loss of therapeutic Olanzapine Decreased level of efficacy olanzapine253. levels103.74– efficacy 76.318. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments Tobacco (smoked) Clozapine Decreased level of Induction of P450 1A2 by Possible loss of therapeutic clozapine318–321 tobacco smoking123.318.322 323 Phenothiazines and Decreased typical most other typical antipsychotic antipsychotics.An Overview of Psychotropic Drug–Drug Interactions TABLE A–4.322. tobacco smoking127.322 efficacy fluvoxamine49. 324–326 including haloperidol Tertiary-amine Decreased level of tricyclic tertiary-amine antidepressants TCAs318.114.321.124.322 Induction of P450 1A2 by Possible loss of therapeutic tobacco smoking65.322 (TCAs) Induction of P450 1A2 by Possible loss of therapeutic tobacco efficacy smoking103.107.

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D. Copyright 2003. American Psychiatric Publishing. Used with permission. Armstrong. Jessica R. American Psychiatric Publishing. Inc. DC. Reprinted from Cozza KL.Appendix B P450 TABLES Kelly L. UGTs. 2003. Scott C. Washington. 2nd Edition. 343 . M. P-Glycoproteins. Cozza. Armstrong SC.D. M.D. Oesterheld. Oesterheld JR: Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s. M.

344 TABLE B–1. Drugs metabolized by 2D6 Antipsychotics Chlorpromazine Clozapine4 Fluphenazine3 Haloperidol3 Perphenazine3 Quetiapine3 Risperidone3 Thioridazine3 Other psychotropics Aripiprazole Atomoxetine Other drugs Analgesics Codeine5 Hydrocodone Lidocaine2 Methadone2 Oxycodone Tramadol6 Cardiovascular drugs3 Alprenolol Bufuralol Carvedilol Diltiazem Encainide Flecainide Metoprolol Mexiletine Nifedipine Nisoldipine Propafenone Propranolol7 Timolol Miscellaneous drugs Amphetamine Benztropine2 Cevimeline Chlorpheniramine Delavirdine2 Dexfenfluramine Dextromethorphan8 Donepezil2 Indoramin Loratadine3 Metoclopramide Minaprine Ondansetron2 Phenformin Tacrine2 Tamoxifen2 Antidepressants Tricyclic antidepressants1 Amitriptyline Clomipramine Desipramine Doxepin Imipramine Nortriptyline2 Trimipramine Other antidepressants Fluoxetine3 Fluvoxamine3 Maprotiline3 Mirtazapine3 Nefazodone Paroxetine Sertraline Trazodone3 Venlafaxine3 Drug–Drug Interaction Primer .

1Tricyclic Drugs metabolized by 2D6 (continued) antidepressants (TCAs) use several enzymes for metabolism. 5O-Demethylated to morphine by 2D6. the tertiary tricyclics by 3A4. a minor pathway.P450 Tables TABLE B–1. 7β-Blockers are partly or primarily metabolized by 2D6. TCAs are also oxidatively metabolized by 1A2 and 2C19. The secondary tricyclics are preferentially metabolized by 2D6. 345 . 2Oxidatively metabolized primarily by 2D6. 6Metabolized to a more active pain-relieving compound. 3Metabolized by other P450 enzymes. M1. 8Used as a probe for 2D6 activity. 3A4 and 1A2 are more prominent. 42D6 is a minor pathway.

with higher doses resulting in more potent inhibition than lower doses. Inhibitors of 2D6 Antipsychotics Chlorpromazine Clozapine Fluphenazine Haloperidol Perphenazine Risperidone Thioridazine Other inhibitors Amiodarone Chlorpheniramine Celecoxib Cimetidine Clomipramine Diphenhydramine Doxorubicin Lansoprazole Lopinavir/Ritonavir Loratadine Methadone Methylphenidate Metoclopramide Mibefradil Pimozide1 Quinidine Ritonavir Terbinafine Ticlopidine1 Valproic acid Yohimbine Antidepressants Amitriptyline Bupropion Desipramine Fluoxetine Fluvoxamine1 Imipramine Norfluoxetine Paroxetine Sertraline2 Venlafaxine Note. 1In vitro evidence exists only for the potential for potent inhibition of 2D6.346 Drug–Drug Interaction Primer TABLE B–2. Names of potent inhibitors are in bold type. 2Sertraline’s inhibition seems to be dose specific. .

N-demethylated) Fentanyl Hydrocodone2 Meperidine8 Methadone Propoxyphene9 Sufentanil Tramadol2 Antiarrhythmics6 Amiodarone Lidocaine Mexiletine2 Propafenone2 Quinidine Antidepressants Amitriptyline1 Citalopram2 Clomipramine1 Doxepin1 Fluoxetine2 Imipramine1 Mirtazapine2 Nefazodone Paroxetine2 Reboxetine Sertraline2 Trazodone2. Drugs metabolized by 3A4 Antipsychotics Aripiprazole Chlorpromazine2 Clozapine4 Haloperidol5 Perphenazine2 Pimozide6 Quetiapine2 Risperidone7 Ziprasidone2. other Buspirone Donepezil2 Galantamine2 Sedative-hypnotics Benzodiazepines Clonazepam Diazepam2 Flunitrazepam2 Nitrazepam2 Triazolobenzodiazepines Alprazolam Estazolam Midazolam Triazolam Other sedative-hypnotics Zaleplon Zolpidem Zopiclone2 Other drugs Analgesics Alfentanil Buprenorphine Codeine (10%.3 Trimipramine1 Venlafaxine2 347 .P450 Tables TABLE B–3.6 Psychotropic drugs.

348 TABLE B–3.10 Drug–Drug Interaction Primer .10 Antiepileptics Carbamazepine Ethosuximide2 Felbamate2 Methsuximide2 Tiagabine2 Valproic acid2 Zonisamide2 Antihistamines Astemizole6.7 Terfenadine6.6.10 Chlorpheniramine Ebastine6 Loratadine6. Drugs metabolized by 3A4 (continued) Other drugs (continued) Antimalarials Chloroquine Halofantrine6 Primaquine Antineoplastics Bulsulfan Cyclophosphamide2 Daunorubicin Docetaxel Doxorubicin Etoposide Ifosfamide2 Paclitaxel2 Tamoxifen2 Teniposide Trofosfamide Vinblastine Vincristine Vindesine Vinorelbine Other drugs (continued) Antiparkinsonian drugs Bromocriptine Pergolide2 Ropinirole2 Selegiline2 Tolcapone2 Antiprogesterone agents Lilopristone Mifepristone Onapristone Toremifene2 Antirejection drugs Cyclosporine Sirolimus (Rapamune) Tacrolimus β-Blockers Metoprolol2 Propranolol2 Timolol2 Other drugs (continued) Calcium-channel blockers Amlodipine Diltiazem2 Felodipine Nicardipine Nifedipine Nimodipine2 Nitrendipine Verapamil2 HMG-CoA reductase inhibitors11 Atorvastatin Cerivastatin10 Lovastatin Pravastatin Simvastatin Macrolide/ketolide antibiotics Azithromycin Clarithromycin Dirithromycin Erythromycin Other drugs (continued) Antibiotics (miscellaneous) Ciprofloxacin Rifabutin Rifampin Sparfloxacin2.

P450 Tables TABLE B–3. 10 Colchicine Other drugs (continued) Other drugs (continued) Macrolide/ketolide antibiotics Protease inhibitors (antivirals) (continued) Amprenavir Indinavir Rokitamycin Lopinavir Telithromycin Nelfinavir Troleandomycin Ritonavir Nonnucleoside reverse Saquinavir transcriptase inhibitors 2 Proton pump inhibitors Delavirdine Esomeprazole11 Efavirenz Lansoprazole11 Nevirapine2 Omeprazole11 Pantoprazole11 Rabeprazole Miscellaneous drugs (continued) Cyclobenzaprine12 Dextromethorphan13 Diclofenac2 Ergots Fluconazole Itraconazole Ketoconazole Levomethadyl6 Meloxicam2 Metoprolol2 Miconazole Montelukast Ondansetron 2 Sildenafil Sibutramine Vesnarinone 349 . Drugs metabolized by 3A4 (continued) Other drugs (continued) Steroids Cortisol Dexamethasone Estradiol Gestodene Hydrocortisone Methylprednisolone Prednisone Progesterone Testosterone Triptans Almotriptan2 Eletriptan Miscellaneous drugs Acetaminophen2 Carvedilol2 Cevimeline2 Cilostazol2 Cisapride6.

11Also metabolized by 2C19. Drug–Drug Interaction Primer . reaction can be a probe for 3A4 activity. 10No longer available in the United States. to a lesser extent. 13N-Demethylation specific for 3A4. 8Not confirmed but strongly suspected to be a primary metabolic pathway. 2D6. 5Also metabolized by 2D6 and 1A2. 3Metabolized by 3A4 to m-chlorophenylpiperazine. UGT= uridine 5′-diphosphate glucuronosyltransferase.350 TABLE B–3. 12Also metabolized by 1A2. 6Potentially toxic to the cardiac conduction system at high levels and therefore should not be used with potent inhibitors of 3A4. Drugs metabolized by 3A4 (continued) Note. 7Also metabolized by 2D6. 4Also metabolized by 1A2 and. 2D6. 1Tertiary tricyclics are metabolized preferentially by 3A4 but are also metabolized by 1A2. 2C19. HMG-CoA = hydroxymethylglutaryl–coenzyme A. 2Also significantly metabolized by other P450 and/or phase II enzymes. and UGTs. 93A4 activates to analgesic norpropoxyphene.

Names of potent inhibitors are in bold type. no longer available in the United States. 2Also a potent inhibitor of 1A2. 6Trade name Kaletra. and 2C9. 4Potent inhibitor of 2C9. 7Also a potent inhibitor of 2D6.P450 Tables 351 TABLE B–4. . 9Also a potent inhibitor of 2D6 and 1A2. Inhibitors of 3A4 Antimicrobials (continued) Macrolide and ketolide antibiotics Clarithromycin Erythromycin Telithromycin Troleandomycin Nonnucleoside reverse transcriptase inhibitors Delavirdine Efavirenz Protease inhibitors Amprenavir Indinavir Lopinavir/ Ritonavir6 Nelfinavir Ritonavir7 Saquinavir Antipsychotics Haloperidol Pimozide Other inhibitors Anastrozole Androstenedione Bromocriptine Chloroquine Cimetidine8 Cisapride Cyclosporine Diltiazem Grapefruit juice3 Methadone Methylprednisone Mibefradil9 Mifepristone Nifedipine Omeprazole Oral contraceptives Phenobarbital Primaquine Propoxyphene Tacrolimus Tamoxifen Valproic acid Verapamil Zafirlukast10 Antidepressants Selective serotonin reuptake inhibitors1 Fluoxetine Fluvoxamine Norfluoxetine Paroxetine Sertraline Other antidepressants Nefazodone Antimicrobials Antibiotics. 3Also an inhibitor of 1A2. 1A2. and 2C19. 10Also an inhibitor of 1A2 and 2C9. 1Also inhibit other P450 enzymes. other Ciprofloxacin2 Norfloxacin3 Quinupristin/ Dalfopristin Sparfloxacin3 Azole antifungals Fluconazole4 Itraconazole Ketoconazole5 Miconazole Note. 2C9. 8Also an inhibitor of 2D6. 5Also an inhibitor of 2C19.

. 3Currently known to potently induce only 3A4. 4Removed from the United States market. Names of potent inhibitors are in bold type. 2Trade name Kaletra. Inducers of 3A4 Other inducers Cisplatin Cyclophosphamide Dexamethasone Efavirenz Ifosfamide Lopinavir/Ritonavir2 Methadone Methylprednisolone Modafinil Nevirapine Pioglitazone Prednisone Rifabutin Rifampin1 Rifapentine1 Ritonavir3 St.352 Drug–Drug Interaction Primer TABLE B–5. 1“Pan-inducers”—also induce most other P450 enzymes. John’s wort Troglitazone4 Antiepileptics Carbamazepine1 Felbamate Oxcarbazepine Phenobarbital1 Phenytoin1 Primidone Note.

2 Clomipramine1 Fluvoxamine3 Imipramine1 Mirtazapine4 Note. 4Also metabolized by 3A4. at least 50% of enzymatic metabolism is through 1A2. 9Contribution of 1A2 metabolism is small. 3Metabolized by other P450 enzymes as well. 8Removed from the United States market. 5Demethylated by 1A2 to norclozapine. to a lesser extent. 2N-Demethylation may be preferentially done by 2C19.P450 Tables 353 TABLE B–6. 2D6. Names of drugs are in bold type if there is evidence that in normal human use of the drugs. . 1Tertiary tricyclic antidepressants (TCAs) are demethylated by 1A2 and 3A4. and 2C19 also metabolize tertiary TCAs. 10 Weaker pharmacological isomer of racemic warfarin. glucuronidated by the glucuronosyltransferase (UGT) 1A4. 6Metabolized 30%–40% by 1A2 and some by 2D6. Drugs metabolized by 1A2 Antipsychotics Chlorpromazine3 Clozapine5 Fluphenazine Haloperidol3 Mesoridazine3 Olanzapine6 Perphenazine Thioridazine3 Thiothixene3 Trifluoperazine3 Ziprasidone7 Other drugs Acetaminophen Phenacetin Caffeine Propafenone9 Cyclobenzaprine Propranolol9 Dacarbazine Riluzole Flutamide Ropinirole Frovatriptan Ropivacaine Tacrine Grepafloxacin8 Melatonin Theophylline Mexiletine Toremifene Mibefradil8 Verapamil9 Naproxen R-Warfarin10 Ondansetron Zolmitriptan Zolpidem9 Antidepressants Amitriptyline1. 2C9. Clozapine is metabolized to clozapine-N-oxide by 3A4 and. 2D6 and others. 71A2 is a minor route of metabolism.

Names of drugs are in bold type if there is evidence that in normal human use. 1Flutamide’s primary metabolite is a potent inhibitor of 1A2. Inhibitors of 1A2 Other drugs Anastrozole Caffeine Cimetidine Fluphenazine Flutamide1 Grapefruit juice Lidocaine Mexiletine Mibefradil Nelfinavir Oral contraceptives Perphenazine Phenacetin Propafenone Ranitidine2 Rifampin Ropinirole3 Tacrine Ticlopidine Tocainide Verapamil Zafirlukast Fluoroquinolone antibiotics Ciprofloxacin Enoxacin Grepafloxacin Lomefloxacin Norfloxacin Ofloxacin Sparfloxacin SSRIs Fluvoxamine Note. TABLE B–8. the drugs are potent inhibitors. SSRI = selective serotonin reuptake inhibitor. 2Scant evidence of 1A2 inhibition. 3Weak inhibitor.354 Drug–Drug Interaction Primer TABLE B–7. . 2Induces through stimulation of PAHs. Inducers of 1A2 Foods Broccoli Brussels sprouts Cabbage Cauliflower Charbroiled foods1 Other inducers Chronic smoking2 Drugs Caffeine Carbamazepine Esomeprazole Griseofulvin Lansoprazole Moricizine Omeprazole Rifampin Ritonavir 1Possibly induce through stimulation of polycyclic aromatic hydrocarbons (PAHs).

NSAID =nonsteroidal anti-inflammatory drug.” most of which are oxidatively metabolized in part or in full by 3A4. 6S-Warfarin is the more active isomer of warfarin. 1Metabolized by other P450 enzymes as well. 5Metabolized by 2C9 to active 17-hydroxyethinylestradiol.P450 Tables TABLE B–9. 4The exception to the “statins. Drugs metabolized by 2C9 Hypoglycemics. 3Also metabolized extensively by phase II enzymes. 355 . 7Metabolized mainly by 3A4 and 1A2. oral 2 Sulfonylureas Glimepiride Glipizide Glyburide Tolbutamide NSAIDs 3 Celecoxib Diclofenac Flurbiprofen Ibuprofen Indomethacin Ketoprofen Mefenamic acid Meloxicam Naproxen Piroxicam Valdecoxib Other drugs Carmustine Dapsone Fluvastatin4 Mestranol5 Paclitaxel1 Phenytoin Tamoxifen Tetrahydrocannabinol Torsemide S-Warfarin6 Zafirlukast ?Zolpidem7 Angiotensin II blockers Irbesartan Losartan Valsartan Antidepressants Fluoxetine1 Sertraline1 Note. R-warfarin is metabolized by 1A2. 2“Glitazones” are metabolized by 2C8 and 3A4.

an inhibitor of 1A2 and 3A4. 1Amiodarone. However. desmethylamiodarone. Inducers of 2C9 Phenobarbital Phenytoin Rifabutin Rifampin Rifapentine Ritonavir Secobarbital ?Valproic acid Carbamazepine Cyclophosphamide Ethanol Ifosfamide . its metabolite. is an insignificant 2C9 inhibitor.356 Drug–Drug Interaction Primer TABLE B–10. Names of potent inhibitors are in bold type. is a clinically relevant 2C9 inhibitor. TABLE B–11. Inhibitors of 2C9 Other inhibitors Amiodarone1 Anastrozole Cimetidine Clopidogrel Delavirdine Efavirenz Fluconazole Fluvastatin Isoniazid Modafinil Phenylbutazone Ranitidine Ritonavir Sulfamethoxazole Sulfaphenazole Sulfinpyrazone Valproic acid Zafirlukast Selective serotonin reuptake inhibitors Fluoxetine Fluvoxamine Paroxetine Sertraline Note.

7Also metabolized by 2B6 and 3A4. Antidepressants Amitriptyline1 Citalopram2 Clomipramine3 Fluoxetine3 Imipramine3 Moclobemide Sertraline3 Trimipramine3 Venlafaxine4 Drugs metabolized by 2C19 Proton pump Barbiturates inhibitors Hexobarbital Esomeprazole5 Mephobarbital Lansoprazole5 Omeprazole5 Pantoprazole5 Rabeprazole5 Other drugs Alprazolam6 Cilostazol Cyclophosphamide7 Diazepam8 Flunitrazepam5 Ifosfamide7 Indomethacin9 Mephenytoin Nelfinavir5 Phenytoin9 Proguanil10 Propranolol Teniposide Tolbutamide9 is also metabolized by 1A2. 3A4. 42C19 is a minor enzyme in venlafaxine’s metabolism. 2D6 and 3A4 are the major enzymes. 1Amitriptyline . 2Also metabolized by 2D6 and 3A4. 8Diazepam is demethylated by 2C19.P450 Tables 357 TABLE B–12. 92C9 is the major route of metabolism. 3Also metabolized by other P450 enzymes. 5Also metabolized by 3A4. 62C19 is a minor enzyme in alprazolam’s metabolism. 3A4 is the major enzyme. Diazepam is also metabolized by 3A4. and 2C19. 10Metabolized by 2C19 to the active compound cycloguanil. but other P450 enzymes and conjugation enzymes are also involved in clearance. Poor metabolizers at 2C19 have been shown to have higher amitriptyline levels.

TABLE B–14. Names of drugs are in bold type if there is evidence of potent inhibition. Inhibitors of 2C19 Other drugs Oral contraceptives Oxcarbazepine Ranitidine Ritonavir Sulfaphenazole Ticlopidine Topiramate Tranylcypromine Valdecoxib Selective serotonin reuptake inhibitors Fluoxetine Fluvoxamine Norfluoxetine Paroxetine Other antidepressants Amitriptyline Imipramine Cimetidine Delavirdine Efavirenz Esomeprazole Felbamate Fluconazole Indomethacin Lansoprazole Modafinil Omeprazole Note. Carbamazepine ?Norethindrone Phenobarbital Inducers of 2C19 Phenytoin Prednisone Rifabutin Rifampin Ritonavir ?Valproic acid .358 Drug–Drug Interaction Primer TABLE B–13.

In cases of overdose or induction of 2E1. 3Metabolism by 2E1 leads to production of a hepatotoxic metabolite. 3A4 and 2C8 are more important. 1Inhibition possibly due to phenyl isothiocyanate. Inhibitors of 2E1 Diethylcarbamate Disulfiram Isoniazid Watercress1 Note. 4Used as a probe for 2E1 activity. Anesthetics1 Enflurane Halothane Isoflurane Methoxyflurane Sevoflurane Drugs metabolized by 2E1 Other drugs and chemicals Acetaminophen2 Aniline Benzene Capsaicin Carbon tetrachloride3 Chlorzoxazone4 Dacarbazine3 Ethanol5 Ethylene glycol Ketones Nitrosamines Verapamil6 defluorinates these anesthetics.P450 Tables 359 TABLE B–15. 62E1 is a minor enzyme in verapamil’s metabolism. 5Metabolized by other hepatic and extrahepatic enzymes. 22E1 12E1 TABLE B–16. . is a minor substrate in normal circumstances. the hepatotoxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) is created. Names of drugs are in bold type if there is evidence of clinically potent inhibition.

Bold type indicates potent inhibitor.360 Drug–Drug Interaction Primer TABLE B–17. . 4Metabolized by 2B6. 32B6 is secondary to 2A6 in C-oxidation. Ethanol1 Isoniazid Obesity Retinoids 1Chronic Inducers of 2E1 Smoking Starvation Uncontrolled diabetes ethanol use induces 2E1. Substrates 2B6 substrates. 22B6 is a minor enzyme. 2C9. 12B6 metabolizes this alkylating agent to its active drug. and inducers Inhibitors Efavirenz Fluoxetine Fluvoxamine Nelfinavir Orphenadrine Paroxetine Ritonavir Thiotepa Inducers Cyclophosphamide Phenobarbital Bupropion Cyclophosphamide1 Diazepam2 Ifosfamide1 Nicotine3 Propofol Sertraline Tamoxifen4 Note. other P450 enzymes and phase II are more important. and 2D6 to a potent active antiestrogenic compound. inhibitors. TABLE B–18.

Appendix C

UGT OR PHASE II (GLUCURONIDATION) TABLES
Jessica R. Oesterheld, M.D.

The content of these tables was obtained from the P450+ Web site http://www. mhc.com/Cytochromes, run by Jessica R. Oesterheld, M.D., and David N. Osser, M.D. Used with permission from Dr. Jessica Oesterheld.

361

362

TABLE C–1.
Chromosome Polymorphism

UGT1A substrates, inhibitors, and inducers 1A1 2 CN–I, CN–II, GS Estrones Amitriptyline Atorvastatin Buprenorphine Cerivastatin Chlorpromazine Clozapine Cyproheptadine Diclofenac Diflunisal Diphenhydramine Doxepin Fenoprofen Gemfibrozil 4–Hydroxytamoxifen Ibuprofen Imipramine Androsterone Progestins Amitriptyline Chlorpromazine Clozapine/Desmethyl metabolites Cyproheptadine Diphenhydramine Doxepin 4–Hydroxytamoxifen Imipramine Lamotrigine Loxapine Meperidine Olanzapine Promethazine Retigabine 1A3 2 1A4 2 1A6 2 Yes Serotonin Acetaminophen Entacapone Flutamide metabolite Ketoprofen Naftazone SN–38 2–Hydroxyestradiols Thyroxine Acetaminophen Clofibric acid Dapsone Diclofenac Diflunisal Ethinyl estradiol Estrone Flavonoids Furosemide Ibuprofen Ketoprofen Labetalol Mefenamic acid Naproxen R–Oxazepam 1A9 2

Some endogenous Bilirubin substrates Estriol Some substrate drugs Acetaminophen Atorvastatin Buprenorphine Cerivastatin Ciprofibrate Clofibrate Ethinyl estradiol Flutamide metabolite Gemfibrozil Nalorphine Naltrexone Simvastatin SN–38 Telmisartan Troglitazone

Drug–Drug Interaction Primer

UGT or Phase II (Glucuronidation) Tables

TABLE C–1.

UGT1A substrates, inhibitors, and inducers (continued) 1A1 1A3 Losartan Loxapine Morphine Nalorphine Naloxone Naltrexone Naproxen Naringenin Norbuprenorphine Promethazine Simvastatin SN–38 Tripelennamine Valproate 1A4 1A6 1A9 Propofol Propranolol Retinoic acid SN–38 Tolcapone Valproate

Some inhibitors

Tacrolimus

Diclofenac Probenecid Sertraline Valproate

Silymarin (milk thistle) Troglitazone

Cyclosporin A Diflunisal Flufenamic acid Mefenamic acid Neflumic acid Silymarin (milk thistle) Tacrolimus

363

364

TABLE C–1.
Some inducers

UGT1A substrates, inhibitors, and inducers (continued) 1A1 Clofibrate Dexamethasone Flavonoids Phenobarbital Phenytoin Ritonavir 1A3 1A4 Carbamazepine Ethinyl estradiol Methsuximide Oxcarbazepine Phenobarbital Phenytoin Primidone Rifampin 1A6 1A9

Dexamethasone Polyaromatic 3–Methylcholanthrene hydrocarbons (3–MC) Polyaromatic hydrocarbons

Note. Italics indicate that the UGT is a minor pathway for the substrate. CN–I= Crigler–Najjar syndrome type I; CN–II=Crigler–Najjar syndrome type II; GS=Gilbert syndrome; UGT= uridine 5′–diphosphate glucuronosyltransferase.

Drug–Drug Interaction Primer

UGT or Phase II (Glucuronidation) Tables

365

TABLE C–2.
Chromosome Some endogenous substrates

UGT2B substrates, inhibitors, and inducers 2B7 4 Androsterone Bile acid 2B15 4 Yes Catechol estrogens 2–Hydroxyestrone Testosterone Dienestrol Entacapone S–Oxazepam Phenytoin metabolites Tolcapone

Polymorphism Yes

Some substrate Chloramphenicol Nalorphine Naloxone drugs Clofibric acid Naltrexone Codeine Naproxen Cyclosporine Norcodeine Diclofenac R–Oxazepam Entacapone Oxycodone Epirubicin Tacrolimus Fenoprofen Hydromorphone Temazepam Tolcapone Ibuprofen Valproate Ketoprofen Zidovudine Lorazepam Zomepirac Losartan Morphine Some inhibitors Amitriptyline Chloramphenicol Clofibrate Codeine Diazepam Diclofenac Fenoprofen Fluconazole Guanfacine Ibuprofen Ketoprofen Some inducers Ganciclovir Phenobarbital Methadone Morphine Naproxen Oxazepam Probenecid Propofol Ranitidine Temazepam Trimethoprim Valproate Rifampin Tobacco smoking

Note. Italics indicate that the UGT is a minor pathway for the substrate. UGT= uridine 5′–diphosphate glucuronosyltransferase.

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Appendix D

P-GLYCOPROTEIN TABLE
Jessica R. Oesterheld, M.D.

The content of this table was obtained from the P450+ Web site http://www. mhc.com/Cytochromes, run by Jessica R. Oesterheld, M.D., and David N. Osser, M.D. Used with permission from Dr. Jessica Oesterheld.

367

368

Drug–Drug Interaction Primer

TABLE D–1.

Some P-glycoprotein nonsubstrates, substrates, inhibitors, and inducers Nonsubstrates Alfentanil Amantadine Chlorpheniramine Citalopram Clozapine Fentanyl Fluconazole Flunitrazepam Fluoxetine Haloperidol Itraconazole Ketoconazole Lidocaine Methotrexate Midazolam Sumatriptan Yohimbine Substrates Aldosterone Amitriptyline Amoxicillin Amprenavir Carbamazepine Chloroquine Cimetidine Ciprofloxacin Citalopram Colchicine Corticosteroids Cyclosporine Digitoxin Digoxin Diltiazem Docetaxel L-Dopa Doxorubicin Enoxacin Erythromycin Estradiol Fexofenadine Fluvoxamine Grepafloxacin Indinavir Irinotecan Lansoprazole Loperamide Losartan Lovastatin Mibefradil Morphine Nelfinavir Nortriptyline Ondansetron Paroxetine Phenytoin Quetiapine Quinidine Inhibitors Amiodarone Amitriptyline Atorvastatin Bromocriptine Chloroquine Chlorpromazine Clarithromycin Cyclosporine Cyproheptadine Desipramine Diltiazem Erythromycin Felodipine Fentanyl Fluoxetine Fluphenazine Fluvoxamine Garlic Grapefruit juice Green tea (catechins) Haloperidol Hydrocortisone Hydroxyzine Imipramine Itraconazole Ketoconazole Lansoprazole Lidocaine Lovastatin Maprotiline Methadone Mibefradil Midazolam Nefazodone (acute) Nelfinavir Ofloxacin Omeprazole Inducers Dexamethasone Doxorubicin Nefazodone (chronic) Phenobarbital Prazosin Rifampin Ritonavir (chronic) St. John’s wort Trazodone ?Venlafaxine

P-Glycoprotein Table 369 TABLE D–1. inhibitors. Some P-glycoprotein nonsubstrates. and inducers (continued) Nonsubstrates Substrates Ranitidine Rifampin Risperidone Ritonavir Saquinavir Tacrolimus Talinolol Teniposide Terfenadine Topiramate Tricyclic antidepressants Venlafaxine Vinblastine Vincristine Inhibitors Orange juice (Seville) Pantoprazole Paroxetine Phenothiazines Pimozide Piperine Probenecid Progesterone Propafenone Propranolol Quinidine Ritonavir (initial) Saquinavir Sertraline Simvastatin Spironolactone Tamoxifen Terfenadine Testosterone Tricyclic antidepressants Trifluoperazine Valspodar Venlafaxine Verapamil Vinblastine Vitamin E Inducers . substrates.

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194–195 Comorbidities. 101–102 Mother Superior. 204–206 Playing With Fire.CASE INDEX Central serotonin syndrome Migraineur. 199–200 Gradual Withdrawal (I). 95–96 Mother Superior. 44–46 Trigeminal Tribulations (I). 82–84 Enuresis (II). 183–184 Inhibitor Induction. 163–164 Conflicting pharmacodynamic effects Transient Ischemic Attack. 137–138 3A4 inducer 24601. 207–208 VIP Psychosis (I). 193–194 Homeless. 189–190 Enuresis (II). 102–104 Conspiracy Theory. 199–200 The Matrix. 42–43 Disequilibrium. 199–200 Hoarder. 200–202 Misguided Measures. 68–69 Dyskinesias. 209–210 2C9 inducer Comorbidities. 211–212 Cholesterol 451. 207–208 VIP Psychosis (I). 137–138 2C19 inducer The Matrix. 44–46 A Plethora of Pills. 42–43 Disequilibrium. 82–84 Do You Hear What I Hear?. 104–105 Seized by Sadness. 200–202 Mother Superior. 102–104 Disequilibrium. 82–84 Enuresis (II). 137–138 2B6 inducer Comorbidities. 127–129 The Matrix. 199–200 Mother Superior. 82–84 Enuresis (II). 96–97 Playing With Fire. 89–91 Inducer added to substrate 1A2 inducer Conspiracy Theory. 172–173 Displacement from D 2 receptor Dopamine Double-Bind. Serotonin. 200–202 Seized by Sadness. 204–206 371 . 203–204 St. 37–39 Trigeminal Tribulations (II). 102–104 Disequilibrium. 204–206 Playing With Fire. 188–189 Gradual Withdrawal (II). 44–46 Smoking Gun (I). 210–211 VIP Psychosis (I). 204–206 Obscenities. 212–213 Hypericum and Hypercholesterolemia.

97–99 See No Evil. 81–82 Mother Superior. Hear No Evil. 97–99 See No Evil. 41–42 Bruiser. 200–202 Mood Destabilization. 158–159 How the Mighty Have Fallen. 235–236 The Matrix. 147–148 Enuresis (I). 162–163 UGT1A4 inducer Conspiracy Theory. 144–145 Hematuria. 99–101 Shake. 113–114 Natural Disaster (II). 47–48 Hematuria. Rattle. Speak No Evil. 31–32 P450 and phase II enzymes Dead Men Tell No Tales. 207–208 Induction of glucuronidation High-Low. 151–152 Drug–Drug Interaction Primer Caffeine Complications. 136–137 Sleeping Beauty. 204–206 Playing With Fire. 30 Worry Wort. 232–233 Probabilities. 187–188 Playing With Fire. 222–223 The Tekulek. 150 Double Fault. 158–159 Java Jitters. 85–87 Inhibitor added to substrate 1A2 inhibitor Anxious About Anthrax. 126–127 Natural Disaster (III). 42–43 Contraceptive Convulsion. 184–185 Complications. 41–42 Bruiser. 104–105 Seized by Sadness. 178–179 The Road to Hell is Paved With Indications. 60–61 Treatment Failure.372 Inducer added to substrate (continued) 3A4 inducer (continued) Natural Disaster (I). 104–105 Sedation. 133 GI Joe. 137-138 A Weighty Matter. 207–208 Trigeminal Tribulations (II). and Roll. 173–174 P-glycoprotein inducer The Curse of Zoster. Rattle. 36–37 Short-Term Gains. 164–165 Fibrillations. 44–46 A Plethora of Pills. 49–50 Just Desserts. 151–152 Cholesterol and Coagulation. 115 Seized by Sadness. 230–231 VIP Psychosis (I). 134–136 Paranoia. 44–46 A Plethora of Pills. 116 Unintended Fertility. 160–161 Compulsive Intoxication. 142–143 The Road to Hell is Paved With Indications. 34–35 Departed Decibels. Speak No Evil. Terminable and Interminable. Hear No Evil. 99–101 Shake. and Roll. 36–37 Short-Term Gains. 143–144 Bedstuck. 136–137 Structural Similarities and Cardiac Calamities. 34–35 The Dizzy Dentist. 55 Nystagmus. 94–95 2C9 inhibitor Bedstuck. 39–40 Compulsive Intoxication. 174–175 . 210–211 Tuberculous Anxiety.

36–37 Short-Term Gains. 99–101 Shake. 41–42 Bruiser. 52–53 Enuresis (I). Speak No Evil. 70–72 Short-Term Gains. 25–26 Bruiser. 117–119 Enuresis (I).. 70–72 See No Evil. 16–17 The Cure Can Be Worse Than the Disease. 28–29 Occupational Hazard. 34–35 The Dizzy Dentist.. Rattle. 108–109 Cranky and Crampy. Rattle. 13–14 Panicked and Confused. 27–28 . 56–57 Bedstuck. 97–99 Sedated Akathisia. 47–48 A Fatal Case of Bronchitis. 129–130 Sleeping Beauty. 220–221 The Road to Hell is Paved With Indications. 133 Dry Heat.. 160–161 Compulsive Intoxication. Hear No Evil. 143–144 Avoidable Tragedy. 123–124 Complications. 122–123 .. and Roll. 197–199 Sedated Akathisia. 36–37 Short-Term Gains. 125–126 Renal Recklessness. 168–169 The Tekulek. 105–106 Hematuria. 66–68 Window. 112–113 Fungal Fatality. 69–70 Grapefruit Gaffe. 49–50 Nystagmus. 232–233 Sensitive. 120–121 Galactic Inconvenience.Lub.. 47–48 Fungal Frustration. 217–218 Too Much of a Good Thing (I). 153–155 373 Vigilance Always. 18–19 The Best Laid Plans. 150 Dry Delirium. 229–230 Galactic Inconvenience.. 69–70 GI Joe. 107–108 Departed Decibels. 130–131 Bedstuck. 109–111 2E1 inhibitor Dry Delirium. 117 Departed Decibels. 148–149 How the Mighty Have Fallen. 131–133 Stymied by Statins (II). 133 Drowsy Dog Trainer. 240–241 Bloated. 58–60 Shake. 60–61 Sleepy. 52–53 3A4 inhibitor Anxious About Anthrax. 144–145 Rumination. 136–137 Sialorrhea. 23–24 Legionnaire. and Roll. 47–48 From Heartbreak to Heartburn. 24–25 The Spirit of Inquiry.. 15–16 Sad and Sore.Dub. 136–137 Palpitations. 151–152 Clumsy. 41–42 Bitter Fruit. 136–137 Stupor. 196–197 Compulsive Intoxication. 94–95 2D6 inhibitor Anergy Through Synergy. 34–35 Crash. 158–159 Horizontal. 21–22 Enuresis (I). 119–120 Insomnia.Case Index 2C19 inhibitor Anxious Accountant (I). 151–152 Clots. 231–232 Oversuppression.

146–147 Transitions. 74–75 The Tremulous Trucker. 139–140 2C9 inducer VIP Psychosis (II). 87 Drug–Drug Interaction Primer Plasma protein displacement Displaced. 73–74 Rash Decision (I). 146–147 2C9 inhibitor Antidepressant Withdrawal Seizure. 140–142 Smoking Gun (III). 180–181 UGT1A4 inhibitor A Little Goes a Long Way. 167–168 Monoamine oxidase inhibitor– clozapine interaction Baffling Hypertension. 50–51 2C19 inhibitor Antidepressant Withdrawal Seizure. 62–64 Surprising Sedation. 145–146 VIP Psychosis (II). 79–80 Lithium toxicity Decaffeination Intoxication. 195–196 Less is More. 50–51 . 181–182 Inotropic Anorexia. 62–64 Nic Fit. 75–76 P450 inhibition High-Low. 22–23 VIP Psychosis (II). 146–147 Transitions. 61–62 Anxious Accountant (II). 213–215 Reversal of induction 1A2 inducer The Law of Unintended Consequences (II). 66–68 The Worst of Both Worlds. 77–78 Lithium blood levels. 93–94 Less is More. 202–203 Diabetes Insipidus Difficulties. 61–62 New and Improved. 76–77 Nauseated Nanny. 165–166 A Tremulous Triathelete. 169–171 High-Low. 171–172 Natural Disaster (IV). 57–58 New and Improved. 85–87 Illusory Interaction. 139–140 2C19 inducer VIP Psychosis (II). 88–89 The Zebras Are Loose. 85–87 Pharmacodynamic synergy Herbal Hemorrhage. 139–140 UGT1A4 inducer Rash Decision (II). 72–73 Too Tired. 46–47 New and Improved. decreasing More Than He Bargained For. 179–180 Smoking Gun (II). 139–140 3A4 inducer Anticonvulsant Withdrawal Intoxication. 32–33 monoamine oxidase inhibitor Resistance. 236–237 Reversal of inhibition 1A2 inhibitor The Law of Unintended Consequences (I). 166–167 P-glycoprotein inhibitor Flagellated. 208–209 Premature Crossover. 238–240 P-glycoprotein transporter Community-Acquired Toxicity.374 Inhibitor added to substrate (continued) 3A4 inhibitor (continued) Vigilance Always.

17–18 3A4 inhibitor Dangerous Disinhibition. 80 Too Many Cooks in the Kitchen. 222–223 375 Symmetry. 111–112 Symmetry. 161–162 substrates of monoamine oxidase inhibitor Cholestatic Catastrophe. 221–222 Restless. 29–30 Stymied by Statins (I). 53–54 Disequilibrium. 134 New and Improved. 182–183 Induction Toxicity. 156–157 Insufficiency. 172–173 . 64–66 2D6 substrate “I Get Delirious. 131–133 prostaglandin synthesis Orthopedic Recovery and Manic Recurrence. 72–73 3A4 substrate Alcohol-Free Intoxication. offsetting Polyuria. 234–235 2C9 inhibitor The Clot Thickens. 64–66 Wired.” 218–219 Postpartum Psychosis. 226–227 Side effects. 153–155 Too Much of a Good Thing (II). 156–157 New and Improved. 53–54 Somatic Sedation. 237–238 tricyclic antidepressant Fatal Error. 19–20 Premature Crossover. 175–177 2C19 inhibitor Alcohol-Free Intoxication. 121–122 Stealing Sister’s Sleepers. 146–147 The Potential Perils of Frugality. 58–60 Substrate added to inhibitor 1A2 substrate Structural Similarities and Cardiac Calamities. 35–36 2B6 inhibitor Optimization. 152–153 Substrate added to inducer 2D6 substrate Antiemetic Arrhythmia. 64–66 Too Much of a Good Thing (I). 191–192 The Worst of Both Worlds. 82–84 False Alarm. 224–225 3A4 substrate Formularies. 124–125 Unplanned Parenthood. 146–147 The Spirit of Inquiry. 225–226 Over-the-Counter Calamity. 91–92 Substrate added to induced enzyme 2E1 substrate All Things in Excess. 177–179 Symmetry. 32–33 Phase II glucuronidation Sensitive. 192–193 Patience. 155–156 aldehyde dehydrogenase substrate Secret Ingredient.Case Index 2D6 inhibitor Dangerous Disinhibition.

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See also Human immunodeficiency virus Acute acetaminophen-induced hepatitis. 344 Anastrozole. 331 interaction with St. 349 Alprazolam. 88–89. 368 Amphetamine. 346. 331 with erythromycin. 353. 353. 347. See Zolpidem Amiodarone. See Acquired immune deficiency syndrome Akathisia. 357 drug–drug interactions with carbamazepine. See Aripiprazole ACE. 365 Anergy. 347. 358. 217–227 Angiotensin-converting enzyme (ACE) inhibitors. 66–68. 359. 357. 339 Alprenolol. 354. 344 Amprenavir. 133. 18–19 Anesthesia. 152–153 Acute ischemic stroke. 368 Anafranil. 175–177. 356. 130–131. 70–72 Alcohol dependence. 117–119. 18–19. 158–160. 351. 161–162 Aldosterone. 24–25.SUBJECT INDEX Page numbers printed in boldface type refer to tables or figures. 193–194. 331. 176 Acute renal failure. 368 Almotriptan. 331 with fluvoxamine. See also Case Studies Index case vignettes. 331 with nefazodone. 365. See Angiotensin-converting enzyme inhibitors Acetaminophen. See Attention-deficit/ hyperactivity disorder AIDS. 344 Amantadine. Abilify. 347. 362. 331 with clarithromycin. 152–153. 108–109. 121–122. See Clomipramine Analgesics. 359. 101–102. 52–53. See also individual drug names drugs metabolized by 2D6. 362. 31–32. 347. 362 Acquired immune deficiency syndrome (AIDS). 53–54. John’s wort. 337 377 . 349. 152–153. 347. 351 Androsterone. 22–23. 348 Amoxicillin. 222–223. 368 Amlodipine. 349. 351. 27–28. 122–123 ADHD. 356 Androstenedione. 331 with phenytoin. 344. 331 with fluoxetine. 15–16. drug–drug interaction with lithium. 368 Ambien. 346. 368 Alfentanil. 368 Amitriptyline.

See also Generalized anxiety disorder Aripiprazole. 247–249 withdrawal seizure. 347 Antibiotics. 336 interaction with grapefruit juice. 348. 111–112. 348 Antiparkinsonian drugs. 158–160. 304 with quetiapine. 348 Antimalarials. 303 with other antipsychotic agents. 352 Antihistamines. 307 with typical antipsychotics. 355. 346 pharmacokinetic features. 357. 348 Drug–Drug Interaction Primer Anxiety disorder. 348 Antiprogesterone agents. 353. 189–190 . 201 Antiarrhythmics. 283. 348. 112–113. 143–144. 359 Anorexia. 105–106. 299–313 with carbamazepine. 337 Aniline. 162–163. 351 Antineoplastics. 194–195. 286 drugs metabolized by 2D6. 224–225 Aspirin. 362. 351. 358. 162–163. 347 inhibitors of 2D6. 351. 28–29 Attention-deficit/hyperactivity disorder (ADHD). 347 drug–drug interactions with carbamazepine. 211–212. 308 with ziprasidone. 283 with fluvoxamine. 172 Atrioventricular heart block. 299. 344. 355 drug–drug interaction with lithium. 155–156. 339 Atrial fibrillation. 208. 299. See also individual drug names atypical. 23–24. See Lorazepam Atomoxetine. 348 Antipsychotics. 28–29. 327 with ziprasidone. 313 drugs metabolized by 2D6. See also individual drug names drug–drug interactions. 277–298 with MAOIs. 31–32.378 Angiotensin II receptor antagonists. 285 with phenytoin. 368 drug–drug interactions with carbamazepine. 179–180 Athletics. 93–94. 301 with olanzapine. 348 Antimicrobials. 336 with nefazodone. 323 with pimozide. 299 with phenytoin. 306 with risperidone. John’s wort. 60–61. 249–250 Antirejection drugs. 320 with fluoxetine. 227 interaction with valproate. 351. 56–58. 354 Antidepressants. 336 with St. 192–193. 353. 61–62 Antiepileptics. 74–75. See Atypical antipsychotics drug–drug interactions. 348 Asthma. 344 drugs metabolized by 3A4. 312 Arrhythmias. 344 Atorvastatin. 214–215. 285. 104–105. 347 inhibitors of 2D6. 346 pharmacokinetic features. See Disulfiram Anthrax. 89–91. 56–57. 117–119. 180–181 Antabuse. 348. 88–89. 299 with haloperidol. 314 with clozapine. 147–148 Ativan. 344 drugs metabolized by 3A4. 332 Astemizole.

277. 333 with nefazodone. 211–212. 279. 97–99. 248 BuSpar. 30. 117. 344 Beta-blockers. 82–84. 354 Bromocriptine. 348 Cancer. 277 with phenytoin. 77–78. 347 Benztropine. 55. 344 Bulimia nervosa. 357 Benzene. 42–43. See Moxifloxacin Azithromycin. 354 complications. 291 with TCAs. 332 with erythromycin. 20. 15–16. 74–75. 362 Bupropion. 200–202. 209–210. 71–72. 131–133. 293 with typical antipsychotics. 81–82. 279 with fluoxetine. 283 with carbamazepine. 142–143. See Trimethoprimsulfamethoxazole Barbiturates. 238–240 Broccoli. 167–168. 346. 123–124. 231–232. See Oncology Capsaicin. 362 Bipolar disorders. 277. 359 Benzodiazepines. 30 Bulsulfan. 354 Caffeine. 334 with lithium. 79–80. 18–19. 68–69. 116. 276. 290 with phenothiazine antipsychotics. 79–80. 332 with MAOIs. 333 with fluvoxamine. 347 drug–drug interaction with carbamazepine. 354 Bufuralol. 348 Buprenorphine. 353. 25–26. 63–64. 107–108. 347. 112–113. 359 . 334 Calan SR. 93–94. 335 with St. 44–46. 276. 333 with phenytoin. 73–74. 105–106. 276. See Clarithromycin Bile acid. 333. 76–77. 204–206. 85–87.Subject Index Atypical antipsychotics. 351. 348 Azole antifungals. John's wort. 169–171. 339 Cabbage. 91–92. See Verapamil Calcium-channel blockers. 131–133 Brussels sprouts. 332 with clarithromycin. 323 with sertraline. 333 interaction with grapefruit juice. 75–76. 202–203. 82–84. 283 with MAOIs. 332. 15–16. 277. 314 379 with duloxetine. 102–104. See also individual drug names pharmacokinetic features. 276 with paroxetine. 308 pharmacokinetic features. 207–208. 276. 226–227. 348. 119–120. 277. 37–39. 153–155. 249 Avelox. See Buspirone Buspirone. 351 Bacterial vaginosis. 22–23. 281 with fluvoxamine. 281. 276 with nefazodone. 348 Biaxin. 360 drug–drug interactions. 61–62. 75–76. 368 Bronchitis. 365 Bilirubin. 62–64. 238–240 Bactrim. 39–40 interaction with clozapine. 58–60.

346. 344. 358. 279. 294. 209–210. 344. 321 with lovastatin. 349. 316. 320. 346. 306. 359 Cardiomyopathy. 44–46. 323 with pimozide. 349 Case studies. 349 Chloramphenicol. 346. 211–212. 356. 365 Chloroquine. 279. 6. 199–200. 348. 364. 362 Cevimeline. 351. 351. 347. 359 Cilostazol. 22–23. See Citalopram Cerivastatin. 299. 143–144. 99–101. 314 with escitalopram. 317 with phenytoin. 355 Celexa. 336 with TCAs. 277. 307. 303. 276. See Ciprofloxacin Ciprofibrate. 320 interaction with grapefruit juice. 362. 238–240. 315 with haloperidol. 314 with buspirone. 362 Ciprofloxacin. See Green tea Catechol estrogens. 356. 352 . 354. 205–206. 302. 318 with sertraline.380 Carbamazepine. 368 drug–drug interactions. 160–161. 314 with duloxetine. 348. 188–189. 335 pharmacokinetic features. 168–169. 312. 97–99. 288. 300. 368 Chlorpheniramine. 318 with risperidone. 25–26. 102–104. 348. 182–183. 281. 192–193. See Case Studies Index Catechins. 329 with ziprasidone. 281. 304. 131– 133. 193–194. 309. 352. 354. 354 Celecoxib. 250 Carbon tetrachloride. 277. 332 with citalopram. 89. 344 Cardizem. 315. 319. 357 Cimetidine. 7. See Diltiazem Carisoprodol. 344. 314 with ethinylestradiol. 319 with topiramate. 317. 287. 315 with hydroxymethylglutaryl– coenzyme A reductase inhibitors. 287 with alprazolam. 349. 368 Chlorpromazine. 144–145. 155–156. 191–192. 348. 353. 368 Cipro. 210–211. 368 Chlorzoxazone. 113–114 Cardiovascular drugs. 146–147. 315 with fluvoxamine. 314 with clozapine. 283. 291. 355 Carvedilol. 316 with nefazodone. 358. 156–157. 365 Cauliflower. 354. 328 Drug–Drug Interaction Primer with typical antipsychotics. 42–43. 63–64. 331 with aripiprazole. 351. 316 with olanzapine. 142–143. 277. 133. 32–33. 136–137. 336 with bupropion. 318 with simvastatin. 336 with mirtazapine. 351 Cisplatin. 314 with atorvastatin. 368 Cisapride. 336 with lamotrigine. 177–178 Carmustine. 318 with quetiapine. 348. 334 with fluoxetine. See also individual drug names drugs metabolized by 2D6. 81–82. 320 with valproate. 283. 346. 344.

140–142. 117. 351 Danshen. 58–60. See Prednisone . 52–53 Deltasone. 357. 19–20. 347. 365 Clomipramine. 352. 82–84. 278. 220–221. 304 with secondary-amine TCAs. 314 with MAOIs. 368 drug–drug interactions. 47–48. 347 Clopidogrel. 277. 308. 41–42. 357. 222–223. See Benztropine Colchicine. 17–18. 153–155. 348 DDIs. 314 with fluoxetine. 247 Clarithromycin. 113–114. 365 Clofibric acid. 365. 284. 112–113. 353. 250 Clozaril. 189–190. 353. 143–144.Subject Index Citalopram. 146–147. 300 with fluvoxamine. 17–18. 116. 34–35. 286. 344. 8. See Indinavir Cyclobenzaprine. 286 with aripiprazole. 324 with pimozide. 136–137. 341 pharmacokinetic features. 300 with MAOIs. 36–37. 348. 277–278 with carbamazepine. 356. 368 drug–drug interactions. 351. 344. 347. 94–95. 353 Cyclophosphamide. 333 with smoking. 357 Clonazepam. 301. 331 with buspirone. 349 Coumadin. 75–76. 173–174 Corticosteroids. 347. 368 Colonoscopy. 39–40. 368 Dacarbazine. See Warfarin Crixivan. 368 drug–drug interactions with alprazolam. 362. 129–130. 145–146. 362. 355. 356 Clotrimazole. 344. 346. 217–218. See Sulindac Clofibrate. 15–16 Congestive heart failure. 115 Comorbidities. 278 with phenothiazine antipsychotics. 360 Cyclosporin A. 284. 171 Dapsone. 69–70. 139–140. 364. 21–22 Codeine. 347. 2 Confusion. 65–66. 368 Cyproheptadine. 229 Clozapine. 351. 28–29. 279. 362 Daunorubicin. 365 Cogentin. 294 with typical antipsychotics. See Clozapine Cocaine. See Drug–drug interactions Delavirdine. 44–46. 160–161. 195–196 Competitive inhibition. 356. 181–182. 111–112. 180–181. 362. 279 with TCAs. 351. 8 with tobacco. 368 Cortisol. 362. 332 Clinoril. 353. 181–182 Coronary artery disease. 358 Delirium. 224–225. 82–84. 102–104. 349. 281. 359 Dalfopristin. 346. 300. 324 381 interaction with caffeine. 299 with carbamazepine. 113–114. 344. 301 with phenytoin. 137–138. 349. 363 Cyclosporine. 165–166. 281. 278 with phenytoin. 348. 348. 349. 309 pharmacokinetic features. 108–109.

123–124. 210–211 Dermatology. 55. 360 Diazepam. 111–112. 115. 190. 279–280. See Phenytoin Dilaudid. 281. 156–157. 29–30. 295 with typical antipsychotics. 142–143. 243–275 patterns of P450 drug–drug interactions. 162–163. 49–50. 172–173. 362 Doxorubicin. 368 Dolophine. 160–161. 27–28. 352. See Valsartan Diphenhydramine. 107–108. 365 Diethylcarbamate. 77–78. 56–57. 156–157. 344. 276. 52–53. 346. 314 with fluoxetine. 349. 55. 123–124. 362. 153. 21–22. 46–47. See Meperidine Depakote. 348. 351. 349. 346. 368 Desmethyl metabolites. 161–162. 357. See Venlafaxine Elavil. 42–43. See Amitriptyline . 76–77. 23–24. 363. 72–73. 30. 344. 360 Effexor. 60–61. 279. See Fluconazole Diflunisal. 69–70. 348. 309 pharmacokinetic features. 349. 280. 46–47. 349 Diabetes mellitus. 5–8 Duloxetine drug–drug interactions. 368 Drug–drug interactions (DDIs). 284 with bupropion. 78. 226–227 Docetaxel. 236–237 Desipramine. See also Case Studies Index onychomycosis. 209–210. 165–166. 358. 348 Ecotrin. 15–16. 368 Dexfenfluramine. 44–46. 352. 229–230. 365 Diclofenac. 130–131. 351. 153–155. 66–68. 279. 279. 360. 365 Dienestrol. 158–160. 178–179. 368 Digoxin. 85–87. 362 Desyrel. 53–54. 348 Disulfiram. 280 with TCAs. See Hydromorphone Diltiazem. 248 Dysthymic disorder. 363 Digitoxin. 80. See Divalproex sodium Depression. 180–181. 181–182 Dilantin. 231–232. 82–84. 346. 169–171. See Methadone Donepezil. 41–42. 53–54. 47–48. See also individual drug names overview of psychotropic interactions. 364. 344. 347. 28–29. 279 with carbamazepine. 202–203. 203–204. 101–102. 89–91 Doxepin. 160–161. 109–111. 359 Drug–Drug Interaction Primer Divalproex sodium. 347 L-Dopa. 368 Dopamine. 163–164 Ebastine. See Trazodone Dexamethasone. 362 Dirithromycin.382 Demerol. 39–40. 362. 281 with fluvoxamine. 280 with paroxetine. 348. 58–60. 359 Diflucan. 231–232 rashes. See Aspirin Efavirenz. 308. 290 with phenothiazine antipsychotics. 355. 284 with MAOIs. 356. 117–119. 368 Diovan. 80. 195–196. 279. 347. 344 Dextromethorphan. 368 Dogoxin. 192–193. 280. 172–173. 344. 344.

276. 359 Enoxacin. 335 with topiramate. 355. 315 . 358. 368 Fexofenadine. 357 Fluoroquinolone antibiotics. 344 Flexeril. 357. 28 Ergots. 364 Flecainide. 344. 279 with TCAs. 278 with phenothiazine antipsychotics. 354 Fluoxetine. 362 Estrones. 362. 368 drug–drug interaction with buspirone. 368 Flagyl. 129–130. 356. 354. 349 Erythromycin. 281 with carbamazepine. 50–51. 348 Ethylene glycol. 362 Ethanol. 359. 217–218. 294 with typical antipsychotics. 47–48. 347. 368 Fenoprofen. 247 Eskalith. 362. 160–161. 237–238. 19–20. 30. 153–155. 348 FDA. 354. 47–48.Subject Index Eletriptan. 121–122 Flunitrazepam. 362. 351. 334 with lamotrigine. 334 with phenytoin. 365. 71–72. 349. 314 with MAOIs. See Phenytoin Epirubicin. 339 Ethosuximide. 156–157. 39–40. 356. 349 E-mycin. 304 with secondary-amine TCAs. 279. 281–282 with alprazolam. 324 with pimozide. 277. 368 Flufenamic acid. 347 Estradiol. 351. 279. 368 Estriol. See Lithium Esomeprazole. 347. 368 Entacapone. 360 drug–drug interactions. 119–120. 358 Estazolam. 365 Fentanyl. 351. 365 Enterococcus faecium. 277–278 with carbamazepine. 309 pharmacokinetic features. See Erythromycin Enalapril. 357. 347. 349. 364 383 drug–drug interaction with carbamazepine. 335. 111–112. 69–70. 147–148. 278 with phenytoin. 349. Food and Drug Administration Felbamate. 134. 352. 335 interaction with St. 360 Ethinylestradiol. See Metronidazole Flavonoids. See individual enzyme names Epanutin. 363 Flumazenil. 332 Escherichia coli. 358 Felodipine. 169–171 Encainide. 98. 65–66. 346. 23–24. See U. 199–200 Enzymes. John’s wort.S. 331 with bupropion. 356. 131–133. 278. 365 Erectile dysfunction. 344 Enflurane. 29–30. 230–231. 348. 166–167 Enuresis. 358. 72–73. 334 with oxcarbazepine. 180–181. 178–179 Escitalopram drug–drug interactions. 281. 158–160. See Cyclobenzaprine Fluconazole. 359 Etoposide. 348. 308. 348. 362. 224–225.

87–88. 99–101. 353. 247 Food. 362 Fluvastatin. See Generalized anxiety disorder Galactorrhea. 285 with bupropion. 356. 360. 354. 279. 284 with mirtazapine. See Saquinavir Fractures. 172–173. 302 with MAOIs. 324 with pimozide. 368 interaction with atorvastatin. 34–35. 355 Glipizide. 287 with olanzapine. 88–89. 156–157 Gastrointestinal disease. See Gastroesophageal reflux disease Gestodene. 279. 276. See also Anxiety disorder Geodon. 133 Gemfibrozil. 295 with tertiary-amine TCAs. 36–37. 355. 358. 65–66. 209–210 GAD. 282. 362 Gabapentin. 346. 247 Fluphenazine. 303 with phenytoin.384 Fluoxetine (continued) drug–drug interactions (continued) with clozapine. 188–189. 60–61. 282. 105–106. 310 Drug–Drug Interaction Primer interaction with caffeine. 344. 151–152. 355 Grapefruit juice. 208 Ginseng. 283. 368 Gastroesophageal reflux disease (GERD). 178–179. 116. 368 drug–drug interactions. 172 Glimepiride. 355 Flutamide. 356 Fluvoxamine. 354 disorders. 35–36. 160–161. 198–199. 304 with risperidone. 69–70 Galantamine. 281. 283–284. 284 with haloperidol. 279. 285. 368 Flurbiprofen. 310 pharmacokinetic features. 307 with TCAs. 353. 334 with tobacco. 351. 282. 184–185. 49–50. 289 with phenytoin. 365 Garlic. 341 pharmacokinetic features. 287 with alprazolam. 295 with typical antipsychotics. 231–232. 315 with clozapine. 46–47. 354. 284. 336 . 44–46. 283. 304 with TCAs. See Glipizide Glyburide. See also individual foods charbroiled. 55. 351. 347 Ganciclovir. 346. 331 with antipsychotics. See Ziprasidone GERD. 285. 285. 349 Ginkgo (Ginkgo biloba). 283. 119–120. 354 Flutamide metabolite. 344. 283 with carbamazepine. 353. 281 with MAOIs. 300 with duloxetine. 124–125. 353 Furosemide. 220–221 Glucotrol. 284. 95–96. 41–42. 362 Generalized anxiety disorder (GAD). 282. 75–76. 354. 25–26. 355 Glomerulonephritis. 285 with typical antipsychotics. 282 with nefazodone. 324 with pimozide. 30 Fortovase. 221–222 Frovatriptan. 354. 300 with duloxetine.

234–235. 346. 237–238 Halcion. 68–69. 368 Griseofulvin. 120–121. 21–22 Hexobarbital. See St. See Ifosfamide Ifosfamide. 365 Gynecology. 368 Hydromorphone. Oral contraceptives bacterial vaginosis. 104–105. 348. 127–129. 229–230. 336 with phenytoin. 368 Hypercholesterolemia. 368 . 347. 302 interaction with tobacco. 151–152 Hepatitis. 332. 336 with simvastatin. 368 Grepafloxacin. 63–64. 347 Hypoglycemics. 365 Ifex. 118. 335 with hydroxymethylglutaryl– coenzyme A reductase inhibitors. 353. 336 with lovastatin. 173–174 Hypnotics. 94–95. 75–76. 7. 344. 353. 194–195 Hypericum perforatum. 221–222. oral. 249 Halothane. See Haloperidol Halofantrine. See also Case Studies Index. See Hydroxymethylglutaryl–coenzyme A reductase inhibitors Human immunodeficiency virus (HIV). 121–122. 152–153. 295. 347. 362. 344. 365 Hydroxymethylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors. 357. 77 Hydrocodone. 368 drug–drug interactions with aripiprazole. 325 with TCAs. 359 Hearing loss. See also Acquired immune deficiency syndrome Hydrochlorothiazide. 337 4-Hydroxytamoxifen. 302.Subject Index with buspirone. 357 HIV. 219. 302. 133 Heparin. 315 with fluvoxamine. 348 Haloperidol. 351. 353. 301 with carbamazepine. 337 interaction with grapefruit juice. 126–127. 347 Hydrocortisone. 352. 365 Hydroxyestradiols. 29–30. 28–29. 122–123. 355 Ibuprofen. 344. 6. 360 Imipramine. John’s wort. 336 Green tea (catechins). See Triazolam Haldol. 222–223. 362. 238–240 premenstrual dysphoric disorder. John’s wort Hypertension. See Human immunodeficiency virus 385 HMG-CoA. 356. 358. 182–183. 152–153 Heroin. 172–173. 346. 362 2-Hydroxyestrone. 335 with carbamazepine. 23–24. 357. 349. 197–199. 15–16. 354. 362 Hydroxyzine. 341 pharmacokinetic features. 355. 354 Guanfacine. 8. 200–202. drugs metabolized by 3A4. 199–200. 89–91. 96–97. 336 with St. 336 with nefazodone. 302 with phenytoin. 348 drug–drug interaction with carbamazepine. 336 with pimozide.

354. 226–227 drug–drug interaction with ACE inhibitors and angiotensin II receptor antagonists. 334 with oxcarbazepine. See Liver function tests Lidocaine. See International normalized ratio Insomnia. 360 of 2D6. 236–237. 329 pharmacokinetic features. 2 P-glycoprotein. 176. 349. 207–208. 358. 349. 127–129. 107–185 International normalized ratio (INR). 76–77. 102–104. 321. 130–131. 166–167 Lipitor. 250–251 Lanoxin. 362 drug–drug interactions with carbamazepine. 344. 368 Isoflurane. 184 Irbesartan. 27–28. 368 Legionella pneumonia. 354. 29–30. 97–99. 356. 357. 66–68. 346 added to a substrate. 337 with loop diuretics. 231–232. 165–166. 165–166 Lithium. 93. 358 Indoramin. See Terbinafine Lamotrigine. 322. See Digoxin Lansoprazole. 158–160. 235–236. 212–213 INR. 25–26. 322 with phenytoin. 368 Indocin. See Clonazepam Labetalol. 355 Irinotecan. 346. 81–82. See Atorvastatin Lisinopril. 321 with valproate. 368 Ketones. 61–62. 66–68. See Lamotrigine Lamisil. 167–168. 91–92. 365 Klonopin. 77–78. 349. 360 2B6. 355. 119–120 Lescol. See also Case Studies Index case vignettes. 120–121. 73–74. 7 UGT1A. 36–37. 362. 79–80. 5–6 description. 321. 362–364 UGT2B. 325 with sertraline. See Fluvastatin Levomethadyl. 203. 359. 82–84. 93–94. 151.386 Imitrex. 368–369 reversal of. 118 Inhibitors. 351. 42–43. 74–75. 368–369 reversal of. 344 Inducers. 351. 6 description. 77–78. 7–8 substrated added to. 321 with ethinylestradiol. 359 Isoniazid. 355. 365 Injuries. 359 Ketoprofen. 204–206. 337 . 362–364 UGT2B. 347. 362 Lamictal. 226–227. 357. 316. 292. 172. 365 Induction toxicity. 349. 124–125 Internal medicine. 7 UGT1A. 360 added to a substrate. 171. See Sumatriptan Indinavir. 2 P-glycoprotein. 360 Itraconazole. 368 Drug–Drug Interaction Primer Kava. 349 LFTs. 348 Linezolid. 360 2B6. 44–46. 351. 368 Lilopristone. 88–89 Ketoconazole. See Indomethacin Indomethacin.

336 with St. 158–160. See Monoamine oxidase inhibitors Maprotiline. 362 Mephenytoin. 225–226.Subject Index with nonsteroidal antiinflammatory drugs. 368 drug–drug interactions with carbamazepine. 163–164. See Clotrimazole Lovastatin. 352 Lopressor. 354. 351. 130–131. 368 Lopinavir. 155–156. 364 Methylphenidate. 21–22. 338 with xanthines. 353 Mellaril. 347. 348. 195–196. 362. 344. 151–152. 347. John’s wort. See Metoprolol Loratadine. 353 Mestranol. 336 with nefazodone. See Fluvoxamine Macrolide/ketolide antibiotics. 355 Metabolic enzymes. 346 Methylprednisolone. 72–73. 354 Loop diuretics. 34–35. 359 Methsuximide. 365. 111 Lomefloxacin. 353. 348. 121–122. 362. 115. 348 Lorazepam. 344. 363. 347. 337 Loperamide. 344. 346. 354 Mibefradil. 344. 91–92. 348–349. 336 interaction with grapefruit juice. 68–69. See 3-Methylcholanthrene 3-Methylcholanthrene (3-MC). 225–226. 3 Methadone. 344. 363 Loxitane. 338 with thiazide and potassiumsparing diuretics. See Loxapine Luvox. 348. 346. 368 Mifepristone. 245. 238–240 Mexiletine. 349 Metronidazole. 346. 351 Major depressive disorder. 349. 351 . 368 Methoxyflurane. 338 with osmotic diuretics. See Thioridazine Meloxicam. 189–190. 344. 118. 368 Lotrimin. 211–212. 348. 3 increased formation. 351. 2 extensive. drug–drug interaction with lithium. 221–222. 222–223. 13–15. See Flumazenil Mefenamic acid. 81–82. 352 Metoclopramide. 87–88. 218–219. See Lithium Liver function tests (LFTs). 363 Melatonin. 229–230. 82–84. 118–119. 357 Mephobarbital. See also individual enzymes Metabolites decreased formation. 50–51. 347. 357 Mesoridazine. 368 Mazicon. 355. 351 Midazolam. 349. 52–53. 19–20. 346. 355 Meperidine. 339 Loxapine. 355. 364 3-MC. 349. 251 Lithium carbonate. 346 Metoprolol. 3 ultrarapid. 64–66. 2 poor. 351. 107–108. 75–76 Lithobid. 351. 237–238 387 MAOIs. 365. 368 Miconazole. 194. 349. 353. 368 Methotrexate. 224–225. 334 pharmacokinetic features. 352. 365 Losartan. 338 interaction with caffeine. 188–189.

66–68. 363 Nefazodone. 287. 365 Nardil. 250–251 Moricizine. 312 interaction with St. 368 Moxifloxacin. 164–165. Slobodan. 363. 287–288 with carbamazepine. 362. 280. 363. 32–33. 289 with hydroxymethylglutaryl– coenzyme A reductase inhibitors. 314–330 pharmacokinetic features. 286. 365 NAPQI. 286 with TCAs. 18–19. 325 pharmacokinetic features. 290 . 44–46 drug–drug interactions. 202–203. 248 Montelukast. 344. 365. 336 with lovastatin. 347. 353. 362 Nalorphine. 355. 353 drug–drug interactions. 296 with venlafaxine. 301 with duloxetine. 362. 336 with MAOIs. 354 Morphine. 365 Naltrexone.388 Migraine headaches. 315. 288 with phenytoin. 23–24. 362. 278. 282 with fluvoxamine. 153 Naftazone. 218–219. 331 with atorvastatin. See Phenelzine Naringenin. 340 pharmacokinetic features. 289 with paroxetine. 50–51. 351. 352. 344. See N-acetylcysteine Myocardial infarction. 316 with fluoxetine. 125–126. 282. 288. See Silymarin Milosevic. 288 with buspirone. 363. See Morphine MSIR. 282 with alprazolam. 284. 287. 363. 347. 289 with paroxetine. 282. 289. 365 Naloxone. 248 Moclobemide. 286 with bupropion. 122–123. 278 with fluoxetine. 221–222. 173–174 Minaprine. 333 with citalopram. 27–28. 197–199 Milk thistle. See N-acetyl-p-benzoquinone Naprosyn. 344 Mirtazapine. 287 with MAOIs. 177–178. 357 Modafinil. John’s wort. 101–102. 161–162. 356. 333 with carbamazepine. See Morphine Mucomyst. 210–211. 153 N-acetyl-p-benzoquinone (NAPQI). 368 drug–drug interactions. 18–19. 290 with sertraline. 292 with stimulants. 276. 316 with fluvoxamine. 363. 284. 173–174 N-acetylcysteine. 358 Monoamine oxidase inhibitors (MAOIs) drug–drug interactions. See Naproxen Naproxen. 349 Mood disorders. 298 with ziprasidone. 220–221. 123–124. 278 with clozapine. 276 with buspirone. 288. 181–182 MS Contin. 336 with bupropion. 284. 81–82 Drug–Drug Interaction Primer Mood stabilizers. 288 with nefazodone. 284 with mirtazapine. 24–25. 280 with escitalopram.

104–105. 351. 368 Neuralgia pain. 365 Norethindrone. 341 pharmacokinetic features. 358 Norfloxacin. 80 Obesity. 360. 95–96. 351. 285. 303. 209 Neurology. 360 Obsessive-compulsive disorder (OCD). 37–39. 349. 347 Nitrendipine. 41–42. 247 Norpramin. See also Case Studies Index case vignettes. 60–61. 348 Nisoldipine. 5 drugs metabolized by. 34–35.Subject Index with phenytoin. See also Tobacco Nicotine patch. 348. 250 Omeprazole. 368 drug–drug interaction discontinuation of paroxetine. 289. 305 with simvastatin. 30. 351 Nimodipine. P-glycoprotein and. 348 Oncology metastatic breast cancer. 344. 7 with paroxetine. 85–87. 348 Nicotine. 344. 35–36. 357. 317 with fluvoxamine. 17–18. 144–145. 56–57. 303. 353 inducers of. 359 Nizoral. 344. 348 Nitroglycerin. 344 Nitrazepam. 289. 46–47. 352 Nicardipine. 355 drug–drug interaction with lithium. 234–235. 13–15. 23–24. 64–66. 62–64. 368 Onapristone. See Gabapentin Nevirapine. 368–369 Norbuprenorphine. See Tamoxifen Noncompetitive inhibition. 351 Nonsteroidal anti-inflammatory drugs (NSAIDS). 353. 349. See Nonsteroidal antiinflammatory drugs NyQuil. 354 Norfluoxetine. 161–162 Nitrosamines. 303 with phenytoin. 368 1A2 enzyme description. 58–60. 354 inhibitors of. 74–75. 325 interaction with tobacco. 2 Nonnucleoside reverse transcriptase inhibitors. 354. 168–169. 41–42. 358. 148–149. See also Case Studies Index Ondansetron. 187–215 Neurontin. 109–111. 164–165. 351. 363 Nelfinavir. 360. 338 Nonsubstrates. 249 Neflumic acid. See Desipramine 389 Nortriptyline. 362 drug–drug interactions. 358 pharmacokinetic features. 57–58. 336 pharmacokinetic features. 140–142 Nicotrol. 6 Norvir. See Ketoconazole Nolvadex. 240–241 testicular cancer. 368 Olanzapine. 354 . 357. See Obsessive-compulsive disorder Ofloxacin. 363 Norcodeine. 102–104 OCD. 126–127. 349. 325 with pimozide. 354. 349. 94–95. 354. 353. 285 with aripiprazole. 349. 303 with carbamazepine. 168–169. 351. 42–43. 93–94 Nifedipine. 227. See Ritonavir NSAIDs. 346.

191–192. 217–218 Palpitations. 15–16. 251 Oxycodone. 365 Oxcarbazepine. 360 description. 354 2C9. 235–236. 365 S enantioner. 53–54. 130–131. 338 Oxazepam. 108–109. 7 pattern 5 (reversal of inhibition). inhibitors. 364 drug–drug interactions with ethinylestradiol. See Nortriptyline Panax ginseng. 358. 34–35. 4 drugs metabolized by. 355 2C19 description. 7–8 Paclitaxel. 352. 195–196. 8 pattern 1 (inhibitor added to a substrate). 346 of 2E1. 191– 192. 172 Panic disorder. 5–8 exception. 322. 354 of 2C9. 229–230. 5 drugs metabolized by. 322 with phenytoin. 352 inhibitors of 1A2. 356 of 2C19. 359 of 3A4. 6 pattern 3 (inducer added to a substrate). 328 pharmacokinetic features. 31–32. 6 pattern 4 (substrate added to an inducer). and inducers. 360 Osmotic diuretics. 358. 230–231. 362. 5 drugs metabolized by. 334 with lamotrigine. 353 2B6 substrates. 348. 177–178. 369 Orap. 5 drugs metabolized by. 347–350 description. 354. 344. 357 2D6 drugs metabolized by. 13–15 Pamelor. 236–237. 30. 166–167. 365 P450 enzymes 1A2 description. 5–6 pattern 2 (substrate added to an inhibitor). 1 inducers of 1A2. 7 pattern 6 (reversal of induction). See Pimozide Orphenadrine. 356 of 2C19. 5 2C9 description. 321. 359 3A4 description. 360 of 3A4. 325 with topiramate. 218–219 Oral contraceptives. 4 Drug–Drug Interaction Primer 2E1 description. 188–189. 355 Pain. 351. 117. 323. 24–25. 358 of 2D6. 351 patterns of drug–drug interactions. See also Gynecology Orange juice. 231–232 Opioid dependence. 365 R enantioner. 344–345 overview. drug–drug interaction with lithium.390 Onychomycosis. 164–165. 358 of 2E1. 193–194 . 5 drugs metabolized by.

195–196. 352. 278. 240–241. 296 interaction with tobacco. 365. 299. 308. 6 with phenothiazine antipsychotics. See Tranylcypromine Paroxetine. 290 with MAOIs. 289. 280 with bupropion. 200–202. 353. 324 with escitalopram. 280 with escitalopram. 278. 163–164. 326 . 277 with citalopram.Subject Index Pantoprazole. 156–157. 282. 333 with carbamazepine. 368 drug–drug interactions. 194–195. 341 pharmacokinetic features. 212–213. 249 Phenylbutazone. 307 with TCAs. 349. 344. 347. 278 with duloxetine. 285 with alprazolam. 279. 356. 288. 280. 357. 353. 247 Paxil. 291. 360. 296 with typical antipsychotics. 75–76. 290 with risperidone. 325 with nefazodone. 325 with hydroxymethylglutaryl– coenzyme A reductase inhibitors. 225–226. 310 pharmacokinetic features. 234–235. 348 Perphenazine. 354 Phenelzine. 213–215. 290 with TCAs. 360. 354 P-glycoproteins. 3 nonsubstrates. 301. 321. 277. 285. 52–53. 196–197. 218–219. 166–167. 290 discontinuation with nortriptyline. 85–87. 358. 289. 325 with oxcarbazepine. 290 with nortriptyline. and inducers. 146–147. 369 Parnate. 324 with fluvoxamine. 232–233. 49–50. 325 with pimozide. 277. 148–149. 323 with citalopram. 355. 291. 356 Phenytoin. 7 with duloxetine. 357. 358. 147–148. 368. 352. See Paroxetine PCP. 279. 358. 368 Phenothiazine antipsychotics. 331 with aripiprazole. 278 with paroxetine. 277. 346. 68–69. 58–60. 369 drug–drug interactions. 325 with mirtazapine. 17–18. 155–156. 317. 324 with ethinylestradiol. 174–175. 351. 101–102. 356. 344. 136–137. 322. 323 with buspirone. 344 Phenobarbital. 323 with bupropion. 57–58. 335 with fluoxetine. inhibitors. 351. 368–369 Phenacetin. substrates. 277. 278. 280 with bupropion. 364. 364. 324 with clozapine. 303. 356. 61–62. See Pneumocystis carinii pneumonia Pergolide. 50–51. 15–16. 347. 246 description. 302. 187–188. 282. 277. 237–238 Phenformin. 324 with haloperidol. 108–109. 369 391 drug–drug interactions. 346. 13–15. 305. 104–105. 150. 337 with lamotrigine. 290 with nefazodone. 278. 325 with olanzapine.

See Fluphenazine Promethazine. 326 with sertraline. See also Case Studies Index case vignettes. 134. 362. 347 . 363 Propafenone. 127. 351. 327. 297. 304 with fluvoxamine. 285 with aripiprazole. 326 with topiramate. 293. See Nifedipine Progesterone. 327. 246 types. 369 Progestins. 365 Pimozide. 352 Piperine. 304. See Kava Piroxicam. 19–20 Potassium-sparing diuretics. 347. 27–28. 251 Phenytoin metabolites. 365. 369 Procardia. 347. 304 with escitalopram. 364 Probenecid. 338 Drug–Drug Interaction Primer Pravachol. 349. See Fluoxetine Psychiatry. 247–251 pharmacokinetic processes. 365 Propoxyphene. 304 with fluoxetine. 351 Primidone. 184–185. 91–92 Postpartum psychosis. 368 Prednisone. 363 Protease inhibitors. 369 drug–drug interactions. See Pravastatin Pravastatin. 111–112. 357. 351 Propranolol. 244–245 drugs metabolized by 2D6. 357 Prozac.392 Phenytoin (continued) drug–drug interactions (continued) with quetiapine. 246–247 metabolic enzymes. 348 Prazosin. 349. 306. 292. 352. 312. 245 P-glycoproteins. 237–238 Prilosec. 344. 346. 363. 305. 304 with nefazodone. 182–183. 175–177 Polyaromatic hydrocarbons. 326 with TCAs. 305 with phenytoin. 279. 307. 305. 112–113. 358 Premenstrual dysphoric disorder. 353. 305 with ziprasidone. 348. 362 Prograf. 282. 363. drug– drug interaction with lithium. 349. 330 with ziprasidone. 279. 349. 344. 355 Pneumocystis carinii pneumonia (PCP). 369 Propofol. 327 with valproate. 353. 328 with typical antipsychotics. 360. 249 Pioglitazone. 297. 348. See Omeprazole Primaquine. 336 pharmacokinetic features. 344 drugs metabolized by 3A4. See Tacrolimus Proguanil. 347. 13–106 Psychotropic agents drug–drug interactions. 331–341 current practical resources. 246 pharmacokinetic features. 243–275. 279. 305 with TCAs. 289. 364 Polyuria. 282. 311. 354. 351 Protonix. 369 Piper methysticum. 313 interaction with grapefruit juice. 328 pharmacokinetic features. 285. 304 with carbamazepine. 326 with risperidone. 125–126. 352. 326 with sertraline. 318 with citalopram. See Pantoprazole Proton pump inhibitors. 357 Prolixin. 120–121.

146–147. 248 Sedatives. 160–161. 139–140. 44–46. 75–76. 279 with escitalopram. 307. 182–183. 116. 349. 347. 235–236 antidepressant withdrawal. 368. 69–70. 351 Rabeprazole. 353 Risperdal. 282. 192–193. See also individual drug names drugs metabolized by 3A4. 94–95. 318 393 with fluoxetine. 354. 207–208. 164–165. 129–130. 369 Rokitamycin. 118–119. See Rifampin Rifampin. 356 Riluzole. 71–72. 36–37. 212–213 Secobarbital. See Rifampin Rifampicin. 351. 144–145. 174–175. See also Dermatology Reboxetine. 307 with paroxetine. See Methylphenidate Ritonavir. 155–156 Reglan. 133. 346. 349. 326 pharmacokinetic features. 167–168. 358 Rifadin. 77–78. 358. 47–48. 358. 360. 61–62. 110–111. 344. 120–121. 137–138. 368. 58–60. 153–155. 191–192. 187–188. 137–138. 351. 369 Quinupristin. 62–64. 344. 318 with phenytoin. 354. 279 pharmacokinetic features. See Quinidine Quinidine. 358. 195–196. 250 Ritalin SR. 169–171. See Cyclosporine Saquinavir. 356. See Mirtazapine Renal failure. 356. 94–95. 27–28. 155–156. 346. 139–140. 187–188. 291. 236–237. 352. 15–16. 196–197. 365. 364. 89–91. 369 drug–drug interactions. 39–40. 347. 200–202. 307 with carbamazepine. 307. 352. 70–72. 61–62 . 354 Ropivacaine. 143–144. 368. 369 Rifapentine. 369 Sarafem. 104–105. 189–190. 122–123 Retigabine. 347. 22–23. 121–122. 347 Reflux esophagitis. See Fluoxetine Schizoaffective disorder. 348. 356 Secondary-amine tricyclic antidepressants (TCAs) drug–drug interactions with citalopram. 352. 352. 104–105. 357 Ranitidine. 365. 282 with aripiprazole. 160–161. 360 Rheumatic heart disease.Subject Index Quetiapine. 353 Salvia miltiorrhiza. 173–174. 346. 136–137 Schizophrenia. 363 Retinoids. 356. 279 interactions. 362 Retinoic acid. See Metoclopramide Remeron. 82–84. 354. 124–125. See Risperidone Risperidone. 347 Seizure disorder. 306 with carbamazepine. 349 Ropinirole. 140–142. 348. 171 Sandimmune. 307 with phenytoin. 68–69. 171 Rifabutin. 232–233. 364. 353. 356. 348 Rashes. 306. 49–50. 148–149. 221–222. 150. 250 Quinaglute. 38–39. 326 pharmacokinetic features. 368 drug–drug interactions with aripiprazole. 369 Rapamune. 306. 349. 348.

357. 102–104. 336 interaction with grapefruit juice. 66–68. 202–203 insomnia. 183–184. 339 with hydroxymethylglutaryl– coenzyme A reductase inhibitors. 247–248 Serzone. 166–167 Starvation. 24–25. 130–131. 362. 369 Sporanox. 359 SIADH. 337 with lovastatin. 182–183. John’s wort. 183–184. 31–32. 339 with MAOIs. 122–123. 352. 356. 292. 333. 277. 318 with lamotrigine. See Doxepin Sinus tachycardia. 293. 127–129. 53–54. 339 Sinequan. 344. 66–68. 363. John’s wort. 339 with ethinylestradiol. 351. 335. 135–136. 203–204. 336 with nefazodone. John’s wort. John’s wort. 348. 247–248 Selegiline. 348 Drug–Drug Interaction Primer Sleep disorders. 286 with MAOIs. 29–30. 18–19. 355. 163–164. See Quetiapine Serotonin. 160–161. 339 Staphylococcus aureus. 349 Stimulants. See also individual statin drugs drug–drug interactions. 27–28. See also individual drug names drug–drug interactions. 297 pharmacokinetic features. 358 interaction with St. See Nefazodone Sevoflurane. 293. 73–74. 126–127. 111–112. 340 pharmacokinetic features. 362 Sertraline. 2331 interaction with alprazolam. 339 with HMG-CoA inhibitors. 346. 362. See Selective serotonin reuptake inhibitors St. 369 drug–drug interactions. 326 with pimozide. See Itraconazole SSRIs. 286 . 363. 354 Spironolactone. 369 drug–drug interaction with carbamazepine. 363 Soma. See Syndrome of inappropriate antidiuretic hormone production Sibutramine.394 Selective serotonin reuptake inhibitors (SSRIs). 336 with St. 349 Silymarin (milk thistle). 292 with phenytoin. 292. 347. 368. 348. 339 with atorvastatin. See Tobacco SN–38. 336–337 interaction with St. 113–114. 60–61. 339 Steroids. 351. 305 with TCAs. 244. 349 Sildenafil. 363 Simvastatin. 356. 340 with selective serotonin reuptake inhibitors. 28–29. 354. 351. 360 Statin drugs. 111–112. 277 with bupropion. 124–125 Smoking. 360. 321 with MAOIs. 331. 291. 88–89. 340 with simvastatin. 14 Sirolimus. 162–163. 291 with carbamazepine. See Carisoprodol Sparfloxacin. 348 Seroquel. 339 with buspirone. 122–123.

348. 363. See Theophylline Theophylline. 302 with MAOIs. 217–227 Symbyax. 294. 296 with paroxetine. drug–drug interaction with lithium. 351. 368–369 UGT1A. 362–364 UGT2B. 355. 297 with typical antipsychotics. 18–19 Tachycardia. 365. 285 with bupropion. 365 Tendinitis. 347 Sulfamethoxazole. 297. 296 with phenytoin. 348. 369 Tertiary-amine tricyclic antidepressants (TCAs) drug–drug interactions. 2 description.Subject Index Stroke. 176 Substance dependence. 360. 344. 353 Thiazide diuretics. 293. 360 Thiothixene. 179–180. 326 with pimozide. 357. 294 with fluoxetine. 291. 248 Testosterone. 311 with ziprasidone. 351. 6 depletion. 353 Thiotepa. 229 Terfenadine. 203. 362 Temazepam. 297. 295 with escitalopram. 368 Surgery. 293 with carbamazepine. 295. 351 Telmisartan. 360 2B6. 2 inducer added to. 354 Tacrolimus. 203–204. 240–241. 344. 277. 369 Terbinafine. 348. 360 accumulation. 358 Sulfinpyrazone. See Cimetidine Talinolol. 365. 125–126. 18–19. 356. 70–72. 280. 365 Sufentanil. See Carbamazepine Telithromycin. 353. 107–108. 21–22. 344. 295 with haloperidol. 92 Synergy. 355 Theodur. See also Case Studies Index case vignettes. See Secondary-amine tricyclic antidepressants. 2 added to an inducer. 20. 369 TCAs. 369 Tagamet. 226–227 Teniposide. 349. 349. 297. 197–199 Substrates. See Fluoxetine Syndrome of inappropriate antidiuretic hormone production (SIADH). 7 added to an inhibitor. 356 Sulfaphenazole. 346 395 Tegretol. 109–111. 356 Sulindac. 296 with phenothiazine antipsychotics. 369 Tetrahydrocannabinol. 346. 14 pharmacokinetic features. 353 . 369 Tamoxifen. 55. 134–136. 348. 305 with sertraline. 283. 341 metabolism of. 338 Thioridazine. 280. 294 with duloxetine. 283. 313 interaction with tobacco. 277. 5–6 P-glycoprotein. Tertiary-amine tricyclic antidepressants Tebinafine. 295 with fluvoxamine. 152–153 Tacrine. 14. 227 Sumatriptan. 319 with citalopram. 6 inhibitor added to. 285.

360 2C9 enzyme description. 362. 192–193. 355 Tourette's disorder. 323. 341 with fluvoxamine. 352. 352 inhibitors of. 328 with oxcarbazepine. 349. 208 Transplantation cardiac. 355. 134 rejection. 341 with olanzapine. 197. 365. 251 Toremifene. 348 TIAs. 358. 357 Trimox. 58–60. 363. 140–142. 349 Trofosfamide. See Trimethoprimsulfamethoxazole Tobacco. 248 Trifluoperazine. 347 Tricyclic antidepressants. 353 Torsades de pointes arrhythmia. 5 . 347 Transient ischemic attacks (TIAs). 220–221 Tranylcypromine. See Transient ischemic attacks Ticlid. 358 Timolol. 348 Troglitazone. 179–180. See Ticlopidine Ticlopidine. 113–114 liver. 344. 347–350 inducers of. 358 Trazodone. 356 2C19 enzyme description. 125–126. 4 drugs metabolized by. 96–97. 328 with phenytoin. 369 Trigeminal neuralgia. 249 Triazolam. 178–179 Trimipramine. 341 with haloperidol. 348. 168–169. 224 Torsemide. 347 Triazolobenzodiazepines. 30. 80. 218–219. and inducers. 346. See also Nicotine interaction with clozapine. 328 interaction with ethinylestradiol. 130–131. 341 Tocainide. 348 TMP/SMX. 347. 341 with tertiary-amine tricyclic antidepressants. See Imipramine Tolbutamide. 353. 369 drug–drug interactions with carbamazepine. 202. 363 Troleandomycin. 354 Tofranil. See Oxcarbazepine Trimethoprim. 145–146. 347. 134–136. 189–190 Drug–Drug Interaction Primer Tramadol. 96–97. 356 inhibitors of. 363 Triptans. 365 Trimethoprim-sulfamethoxazole (TMP/SMX). 175–177. 134–136 renal. 369 pharmacokinetic features. inhibitors. 8. 365 Topamax. 344. See Topiramate Topiramate. 355 inducers of. 116. 5 substrates. 172. 5 drugs metabolized by. 164–165 2B6 enzyme description. 354. See Amoxicillin Tripelennamine. 327. 137–138. 209 Trileptal. 341 with typical antipsychotics. 107–108. 172–173. 344. 362 Tiagabine. 368 pharmacokinetic features.396 3A4 enzyme description. 360. 37–39. 319. 354. 348. 351 Thyroxine. 351 Tuberculosis. 344. 357 Tolcapone. 130–131. 335 pharmacokinetic features.

See Bupropion Xanax. 117. 2–3 Vasotec. 245 description. substrates. 329 with lamotrigine. 348 Viramune. 369 Vindesine. See Uridine 5′-diphosphate glucuronosyltransferases Ultram. 251 Valproic acid. 368. 4 drugs metabolized by. 184–185 R enantiomer. 72–73. 73–74. 347 Zantac. 359 Wellbutrin SR. 351. 359 inducers of. 362–365 UGT2B. 348 Vinorelbine. 97–99. 320. 363. 357 inducers of. 91–92. See Nevirapine Vitamin E. 356 Zaleplon. 165–166. 176–177. 355 Valspodar. 104–105. 369 Versed. 344. 93–94. See Acetaminophen UGT1A. 358 inhibitors of.S. 217–218 Vinblastine. and inducers. 172. 160–161. 358 Valium. 327. See Bupropion Wellbutrin XL. 369 drug–drug interactions. 355 Watercress. Food and Drug Administration (FDA). 346. 322. 166–167 Variability. 365 . 330 interaction with aspirin. 202–203. See Midazolam Vesnarinone. 348. 332 pharmacokinetic features. 346 2E1 enzyme description. 151–152. 351. See Diazepam Valproate. 100. 98 Valdecoxib. 158–160. 249 Verapamil. 365 UGTs. 353 S enantiomer. 87–88. and inducers. 348. 329 with phenytoin. 338 Yohimbine. 369 397 Vancomycin. 346. 207. See Lisinopril Zidovudine. 347. 346. 351. 85–87. See Enalapril Venlafaxine. 360 inhibitors of. 205. 355. 167–168. 365 drug–drug interactions with carbamazepine. 91–92. 298 pharmacokinetic features. 353. inhibitors. 358 2D6 enzyme description. 5 drugs metabolized by. 203 drug–drug interaction with lithium. 357. 348. 354. 3 U. substrates. See Ranitidine Zestril. 348. 354. 344–345 inhibitors of. See Alprazolam Xanthines. 28–29. 359 Tylenol. 369 Warfarin. 358 Valsartan. definition. See Tramadol Uridine 5′-diphosphate glucuronosyltransferases (UGTs). inhibitors. with MAOIs. 356.Subject Index drugs metabolized by. 171. 355. 349 Vicodin. 32–33. 369 Vincristine. 359. 18–19. 368 Zafirlukast. 236–237.

312 with carbamazepine. 353. 355 Zomepirac.398 Ziprasidone. See Simvastatin Zolmitriptan. 250 Drug–Drug Interaction Primer Zocor. See Bupropion Zyprexa. 365 Zonisamide. 353 drug–drug interactions. See Sertraline Zolpidem. 287 with aripiprazole. 297. 347 Zyban. See Olanzapine Zyvox. 347. 313 with typical antipsychotics. 124–125. 353 Zoloft. 313 with TCAs. 347. 312. 313 pharmacokinetic features. 312 with phenytoin. 348 Zopiclone. 311. 320 with MAOIs. 29–30. See Linezolid . 187–188. 312. 287. 44–46. 305. 328 with pimozide.

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