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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antipsychotics. Now the chapters represent clinical orientations. a chance to revise and improve on one’s original work. due either to redundancy or to flaws that became apparent only recently. 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. There is something in these cases for everyone. The cases have also been organized in an entirely different manner. I continue to hope that a case series format will help to bring the material alive in a way that dryer. didactic material cannot. A challenge has been to make this version better than the first. 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. This review contains the metabolic pathways and inhibitory and inductive profiles for antidepressants. ethinylestradiol. statins). This is not to say that readers should limit themselves only to the chapters that represent their specific interests. 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. Of special interest is Appendix A. tobacco.INTRODUCTION Second editions present a rare opportunity in life. It has also been nice to fix a few unfortunate errors that crept into the original. Every patient is different. 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. 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. and cases that might be of particular interest to a subspecialty within the field of medicine have been grouped accordingly. Toward that end. There are 29 new cases and 31 of the old cases have been deleted. All of the old caveats still apply.g. The cases were previously arranged by mechanism of interaction.. Some DDIs that will prove troublesome or even dire for one patient may be well tolerated or even beneficial for anix . there have been many changes.

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

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

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

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

Quinidine is an extremely potent 2D6 inhibitor (von Moltke et al. inhibitors. Vandamme et al. and inducers. 1995). and quinolones. macrolides. Several of the selective serotonin reuptake inhibitors (SSRIs) are significant inhibitors of 2D6 (Lam et al. 1986). John’s wort. Common substrates include tertiary-amine TCAs. 1995. The genetics of 3A4 are complex. Typical substrates include tricyclic antidepressants (TCAs. Although there are no actual poor metabolizers. carbamazepine. rifampin. The 2D6 enzyme constitutes only 1%–2% of the P450 complement of the liver. protease inhibitors. there is vast (10. phenothiazines (Dahl-Puustinen et al. 1994). 2003). 2D6 is the usual starting point for any journey into the world of P450. as are TCAs (Lamard et al. 1991). then 3A4 often serves as the backup enzyme. calcium-channel blockers. either by virtue of potent exogenous inhibition or polymorphisms that code for a poor metabolizer phenotype. There are no verified inducers of 2D6 (Madan et al. many antipsychotics. 1993). and some of the antifungals. 2002). 2002). protease inhibitors. and various antiarrhythmic agents (Funck-Bretano et al. triazolobenzodiazepines. 1989. because this was the first P450 enzyme with which psychiatrists became familiar. Common inducers include several anticonvulsants. . and there is also a significant 3A4 presence in the gut (DeVane and Nemeroff 2002). macrolides. and ritonavir (Cozza et al. 1989.4 Drug–Drug Interaction Primer BRIEF REVIEW OF SPECIFIC P450 ENZYMES 2D6 Although not the most important of the P450 enzymes. β-blockers (Lennard et al.to 30-fold) variability in the efficiency of 3A4 functioning across the human population (Ketter et al. Shin et al. 2003). Fourteen percent of Caucasian individuals are poor metabolizers for 2D6. yet it is involved in a number of clinically significant drug interactions. It constitutes roughly 25%–30% of the liver’s P450 complement. St. most 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors. Common inhibitors include some of the SSRIs and nefazodone. When other enzymes that would ordinarily serve as the primary catalysts for the metabolism of various drugs are unavailable. 3A4 The enzyme 3A4 is the workhorse of the P450 system. von Bahr et al. 1993. Sawada and Ohtani 2001). There is a vast array of 3A4 substrates. Dahl et al. whereas 1%–3% of all individuals are ultrarapid metabolizers (Eichelbaum and Evert 1996). and steroid compounds.

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

If the substrate is titrated to specific blood levels or to therapeutic effect. 1995). 1A2. 2002. Because paroxetine inhibits the ability of 2D6 to metabolize nortriptyline. then toxicity is less likely to arise. 1998. Yasui-Furukori et al. Kudo and Ishizaki 1999). Venkatakrishnan et al. Example: Nortriptyline Is Added to Paroxetine Nortriptyline is a 2D6 substrate (Sawada and Ohtani 2001. 1995). . leading to an increase in the blood level of nortriptyline (Leucht et al. Lucas et al. 2003). Spina et al. 2000). 1998. Pattern 3: An Inducer Is Added to a Substrate Adding an inducer to a substrate generally results in decreases in substrate levels.6 Drug–Drug Interaction Primer Example: Paroxetine Is Added to Nortriptyline Nortriptyline is a 2D6 substrate (Sawada and Ohtani 2001. 1999). or with an appreciation that an inhibitor is present. This may lead to clinical decompensation (Hesslinger et al. the added nortriptyline generates a significantly higher nortriptyline blood level than would occur if the paroxetine was not already present (Leucht et al. and haloperidol is metabolized by 3A4. 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. and paroxetine is a 2D6 inhibitor (von Moltke et al. 1996). The addition of paroxetine impairs the ability of 2D6 to metabolize nortriptyline. 1A2. Example: Carbamazepine Is Added to Haloperidol Carbamazepine induces 3A4. Parker et al. 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. and phase II glucuronidation (Hachad et al. and paroxetine is a 2D6 inhibitor (von Moltke et al. and phase II glucuronidation (Desai et al. 1999. 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. Toxicity may result unless appropriate caution is taken. 2D6. Venkatakrishnan et al. 2001. 2000). 1999).

Pattern 5: Reversal of Inhibition Coadministering a substrate and an inhibitor. 1998. so as to achieve equilibria. Lucas et al. 1998. 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. Yasui-Furukori et al. Venkatakrishnan 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. 2D6 is then available to more efficiently metabolize the nortriptyline.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. and then discontinuing the inducer results in gradually (over 1–3 weeks) de- . have been coadministered at appropriate doses. thus generating a significantly lower haloperidol blood level at that haloperidol dose than would occur if carbamazepine was not already present (Hesslinger et al. leading to a significant decrease in the nortriptyline blood level (Leucht et al. resulting in a cessation of 2D6 inhibition. a 2D6 substrate (Sawada and Ohtani 2001. yielding an appropriate nortriptyline blood level and clinical efficacy. 2003). Pattern 6: Reversal of Induction Coadministering a substrate and an inducer. Example: Paroxetine Is Discontinued in the Presence of Nortriptyline Paroxetine. 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. a 2D6 inhibitor (von Moltke et al. so as to achieve equilibria. or with an appreciation that an inducer is present. 1A2. 1995). The paroxetine is then discontinued. possibly producing a subtherapeutic nortriptyline level and a loss of clinical efficacy. when a given dose of haloperidol is administered. If the substrate is titrated to specific blood levels or to clinical effect. and phase II glucuronidation (Desai et al. 2002. 2000). Example: Haloperidol Is Added to Carbamazepine Carbamazepine induces 3A4. then dosing is more likely to be effective. and phase II glucuronidation (Hachad et al. Spina et al. 2D6. Kudo and Ishizaki 1999). 1999). 1996). 2001. and nortriptyline. 1999. and haloperidol is metabolized by 3A4. Parker et al. 1A2. Thus.

The Exception When pro-drugs (e. Oesterheld JR: Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s.. possibly to a toxic degree (Zullino et al. 2nd Edition. 2001 Batty KT. P-Glycoproteins. resulting in a cessation of 1A2 induction. Washington. The Pattern 3 concern is toxicity. 2003 . Ptak LR. Clin Pharmacokinet 29(suppl):20–25. et al: The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects. yielding an appropriate clozapine blood level and clinical efficacy. Tybring G. 1998 Christensen M. et al: Olanzapine: pharmacokinetic and pharmacodynamic profile. DC. 1995 Cadle RM. 1994 Callaghan JT. American Psychiatric Publishing. Zevin and Benowitz 1999). Rodriguez-Barradas MC. not loss of efficacy. unless blood levels are followed and/or substrate doses are decreased in anticipation of the reversal of induction. tramadol. leading to increased levels of substrate and decreased metabolite formation. 1999 Chetty M. Br J Clin Pharmacol 39:305–311. The Pattern 1 concern is loss of efficacy. Clin Pharmacokinet 37:177–193. This leads to decreased metabolism of clozapine and a resulting increase in the blood level of clozapine. 1995 Brosen K: Drug interactions and the cytochrome P450 system: the role of cytochrome P450 1A2. Seymour MA: Phenytoin autoinduction. Example: Smoking Is Discontinued in the Presence of Clozapine A two-pack-per-day cigarette smoker has been taking a stable dose of clozapine. cyclophosphamide) are the substrates in question. 2002 Cozza KL. not toxicity. Bergstrom RF. and so forth. 2002). UGTs. and cigarette smoking induces 1A2 (Schrenk et al. 1997). Ann Pharmacother 28:191–195. 1998. Armstrong SC. This may result in substrate toxicity if the substrate has a low therapeutic index. Sharma RP: Cytochrome enzyme genotype and the prediction of therapeutic response to psychotropics. the clinical concerns are reversed. hydrocodone. Mihara K. Psychiatr Ann 31:715–722. Miller R. Ilett KF.8 Drug–Drug Interaction Primer creased amounts of available enzyme.g. REFERENCES Alam DA. Ther Drug Monit 20:60–62. Clozapine is a 1A2 substrate (Eiermann et al. Davis TM. Zenon GJ 3rd. Clin Pharmacol Ther 71:141–152. Smoking is then discontinued. et al: Fluconazole-induced symptomatic phenytoin toxicity. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19).

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Bouquet S. 1999 Lam YW. Xenobiotica 16:435–447. et al: Cytochrome P450 2D6. Graham R. Neuvonen M. timolol. 1998 . Br J Clin Pharmacol 46:55–62. Birkett DJ: The use of caffeine as a metabolic probe for human drug metabolizing enzymes. Shimamoto J. Kobayashi K. et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. Shimada N. Silas JH. Pritchard P. 1998 Madan A. et al: Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. 1996 Nakajima M. Tucker GT. Carroll K. Backman JT. Brosen K: Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro. Clin Pharmacol Ther 69:194–200. Preston T. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Clin Pharmacokinet 37:435–456. Pharmacotherapy 22:1001– 1006. Ieiri I. 1995 Lennard MS. 2002 Lamard L. Morike K. Bergstrom RF: A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism. Nielsen TL. 2003 Mamiya K. Hackl HJ. Drug Metab Dispos 31:421–431. et al: Involvement of CYP1A2 in mexiletine metabolism. 1999 Lucas RA. Ohtani H: Pharmacokinetics and drug interactions of antidepressive agents (in Japanese). propranolol and atenolol. et al: CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6. Eur J Clin Pharmacol 54:735–740. 1998 Miners JO. 2001 Parker AC. Epilepsia 39:1317–1323. et al: Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients. Nippon Rinsho 59:1539–1545. Br J Clin Pharmacol 45:176– 178. Ann Med Psychol (Paris) 153:140–143. its role in psychopharmacology [in French]. 1998 Rasmussen BB. Eur J Clin Pharmacol 53:361–367. Gilfillan DJ. Eur J Clin Pharmacol 54:639–643. Valdes R Jr: Pharmacogenetics in the practice of laboratory medicine. Gaedigk A. Psychopharmacology (Berl) 147:378–383. 2000 Linder MW. Steimer W. 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: Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test.10 Drug–Drug Interaction Primer Kudo S. 1998 Sawada Y. 2001 Schrenk D. Gen Pharmacol 27:245–249. 1998 Niemi M. 1986 Leucht S. Ereshefsky L. Ishizaki T: Pharmacokinetics of haloperidol: an update. Perault MC. et al: Debrisoquine polymorphism and the metabolism and action of metoprolol. Brockmeier D. Mol Diagn 4:365–379.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

ultimately threatening to stop all of her medications unless he addressed this issue to her satisfaction. Oesterheld. She also was taking an oral contraceptive that contained ethinylestradiol. The addition of topiramate led to an increase in the amount of 3A4 that was available to metabolize the ethinylestradiol. chemical inhibitors. 2000 Guengerich FP: Metabolism of 17 α-ethinylestradiol in humans.R. Six weeks later. Topiramate has been found to decrease blood levels of ethinylestradiol by up to 30% (Rosenfeld et al. Walker SA. resulting in a decrease in the blood level of the ethinylestradiol. One month after discharge. Doose DR. Granda BW. et al: Zolpidem metabolism in vitro: responsible cytochromes. Life Sci 47:1981– 1988. and divalproex sodium (Depakote). she did not gain any further weight. personal communication. 95 µg/mL) after a recent psychiatric hospitalization. the patient was surprised to discover that she was having breakthrough bleeding at an irregular time in her cycle (J. even though the dosage of ethinylestradiol had remained unchanged throughout. titrating up to a dosage of 200 mg/day. Ethinylestradiol is a 3A4 substrate (Guengerich 1990). and topiramate is a 3A4 inducer (Benedetti 2000). References Benedetti MS: Enzyme induction and inhibition by new antiepileptic drugs: a review of human studies. Epilepsia 38:317–323. she noticed that she had gained 10 pounds. 1997). The psychiatrist rather reluctantly added topiramate (Topamax). 1997 . 1. Discussion This is an example of an inducer added to a substrate. She complained to her psychiatrist at length about this weight gain. She did not experience any difficulties with cognition or paresthesias.30 Drug–Drug Interaction Primer von Moltke LL. 10 mg qhs. Greenblatt DJ. This decline in the ethinylestradiol component of the patient’s oral contraceptive led to her episode of breakthrough bleeding. et al: Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Fundam Clin Pharmacol 14:301–319. 1990 Rosenfeld WE. Br J Clin Pharmacol 48:89–97. and in vivo correlations. Although the patient did not lose weight.000 mg/day (blood level. May 2002). 1999 A WEIGHTY MATTER A 27-year-old woman with a history of bipolar I disorder and bulimia nervosa was taking olanzapine (Zyprexa).

Discussion This is an example of an inducer added to a substrate. 2002 Dresser GK. The friend strongly suggested that she try St. Nemeroff CB: 2002 guide to psychotropic drug interactions. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. and within another week she was having daily attacks. Prim Psychiatry 9:28–57. which the psychiatrist compensated for by increasing the dosage of the substrate (alprazolam) and discontinuing the inducer (St. Her generalized anxiety was similarly heightened. he referred the patient to a psychiatrist. Markowitz et al. prescribed by her primary care physician. John’s wort per the package instructions. she began to experience an increased frequency of panic attacks (one every other day). The increase in active 3A4 led to increased metabolism of the alprazolam. and then her baseline 0. 0. John’s wort is a 3A4 inducer (Moore et al.5 mg qid thereafter. Clin Pharmacokinet 38:41–57. No other significant vegetative symptoms of depression were present. John’s wort (Hypericum perforatum). 2000 . Roby et al. she began to take the St. John’s wort stimulated increased production of 3A4. After breaking up with her boyfriend of 3 years. and he increased her standing alprazolam to 1 mg qid for 1 week. she developed significant dysphoria and anhedonia. She was discussing her feelings of rejection and abandonment with her best friend. References DeVane CL. then 0.5 mg qid. After a thorough intake. When she reported her difficulties to her physician. In 2 weeks. 2003). Addition of the St. This subtherapeutic blood level of alprazolam failed to prevent the recurrence of her panic attacks. 2000. the psychiatrist recommended discontinuing the St. Spence JD. 2000). Once the amount of 3A4 available to metabolize the alprazolam had returned to baseline levels. a devotee of homeopathy. John’s wort. These instructions effectively prevented further panic attacks and treated her pervasively anxious state.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). which resulted in a decrease in the blood level of alprazolam over the course of 1–2 weeks (DeVane and Nemeroff 2002. Alprazolam is a 3A4 substrate (Dresser et al. John’s wort). the patient was then able to resume her usual alprazolam dosing. and St.75 mg qid for 10 days. 2000). Without discussing it with her physician.

a competitive inhibitor of 3A4 (von Moltke et al. 2003 Moore LB. and her fatigue and “forgetfulness” remitted even before the nefazodone taper was completed. the patient reported mildly increased fatigue and “forgetfulness” that she attributed to her depression. 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. a 3A4 substrate (Bristol-Myers Squibb 2001). He ordered a carbamazepine blood level. in the past. However. 11. She had responded well to nefazodone (Serzone). 1988. 2000). was started at a dosage that previously had been effective. 2000 THE WORST OF BOTH WORLDS A 42-year-old woman who was taking 1. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Additionally. Anderson GD. primarily a 3A4 substrate (although . although the psychiatrist wondered if it was that simple. before she developed trigeminal neuralgia. Jones SA.000 mg/day of carbamazepine (Tegretol. Her psychiatrist again prescribed nefazodone.1 µg/mL). This resulted in a lower nefazodone blood level and an ineffective antidepressant trial. but even after 6 weeks at that dosage there was no improvement in her depressive symptoms. when nefazodone. 2000 Roby CA. DeVane CL. Ucar et al. et al: St. nefazodone. First. 1996). She eventually responded well to a dosage of 150 mg/day. He tapered and discontinued the nefazodone and started the patient on venlafaxine (Effexor). which had risen to 14. Second. was added to carbamazepine. the presence of carbamazepine. a 3A4 inducer (Arana et al. Discussion This is a combined example of a substrate (nefazodone) added to an inducer (carbamazepine) and an inhibitor (nefazodone) added to a substrate (carbamazepine). for trigeminal neuralgia experienced a recurrence of her depression. Donovan JL. A further dosage increase to 600 mg/day yielded no further improvements. John’s wort: effect on CYP3A4 activity. most recent blood level. 1996. Spina et al. 2004). JAMA 290:1500– 1504.1 µg/mL. Clin Pharmacol Ther 67:451–457. et al: Effect of St John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. titrating to a dosage of 500 mg/day as before. Studies have shown a greater than 10-fold decrease in nefazodone blood levels from baseline when nefazodone is coadministered with carbamazepine (Laroudie et al. et al: St. 500 mg/day. Proc Natl Acad Sci USA 97:7500–7502. Kantor E. Goodwin B.32 Drug–Drug Interaction Primer Markowitz JS.

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

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

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

and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. von Moltke 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). 1998). even though the clozapine dosage had remained constant throughout (Heeringa et al. the blood level of clozapine was found to be 2. the addition of the fluvoxamine led to an impairment of clozapine’s metabolism by these P450 enzymes. 2002 Jeppesen U. Tybring G. Jerling et al. Olesen and Linnet 2001).8 mEq/L).112 ng/mL. et al: A fluvoxamine-caffeine interaction study. 600 mg/day (blood level. Pharmacogenetics 6:213–222. but the psychiatrist reassured him that this was a commonly encountered side effect with fluvoxamine and that the sedation should be transient. 1999. Enzymes 3A4 and 2C19 are also significant contributors. Loft S. Fluvoxamine is a strong inhibitor of 1A2. 1994. resulting in a more than fourfold increase in the clozapine blood level. Niemi et al. After the first 5 days. 2C9. On day 11. Thus. 1995). 1996 Miners JO. several repetitive. bipolar type. His family called 911. 2002. which he titrated to a dosage of 150 mg/day over a 10-day period.36 Drug–Drug Interaction Primer Christensen M. 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. and lithium (Eskalith). The psychiatrist thought it likely that these behaviors were a side effect of the clozapine. RATTLE. 1997. and flooding the toilets with toilet paper). 2001. excessive hand washing and hair brushing. experienced a positive response to clozapine (Clozaril). Clozapine’s metabolism occurs primarily at 1A2. However. and an ambulance transported him to the nearest emergency room. AND ROLL A 37-year-old outpatient with schizoaffective disorder. He therefore decided to treat these compulsive behaviors by adding fluvoxamine (Luvox). There. Poulson HE. after several previously unsuccessful medication regimens. Mihara K. Discussion This is an example of an inhibitor added to a substrate. however. the patient experienced a grand mal seizure. with 2D6 and 2C9 playing only minor metabolic roles (Eiermann et al. Birkett DJ: The use of caffeine as a metabolic probe for human drug metabolizing enzymes. 900 mg/day (blood level. Clin Pharmacol Ther 71:141–152. Gen Pharmacol 27:245–249. After an initial period in which the patient expe- . Wetzel et al. 502 ng/mL). 1996 SHAKE. 0. the patient complained about significant sedation. perseverative ritual behaviors began to emerge (for example.

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

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

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

the patient’s clozapine blood level returned to baseline. J Pharmacol Exp Ther 266:964–971.40 Drug–Drug Interaction Primer (589 ng/mL). These factors explain why the addition of a generally stimulating substance (caffeine) led to paradoxical sedation and anergy. and drug interactions. Br J Clin Pharmacol 49:59–63. 1999 Hagg S. 2004 Stevens JC. References Eiermann B. Rose DM. Engel G. et al: Effect of caffeine-containing versus decaffeinated coffee on serum clozapine concentrations in hospitalised patients. Nordmark A. 1993 . ataxia. With the removal of the competitive inhibitor.) However. 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. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. even though there had been no increase in the dosage. Birkett DJ: The use of caffeine as a metabolic probe for human drug metabolizing enzymes. and his symptoms remitted. 1996 Odom-White A. von Moltke LL. caffeine. Br J Clin Pharmacol 56:679–682. Harmatz JS. Gen Pharmacol 27:245–249. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. J Clin Pharmacol 41:823–832. a probe drug for CYP1A2 activity. J Clin Psychiatry 57:175–176. 2000 Hartter S. Basic Clin Pharmacol Toxicol 94:13–18. 1996 Olesen OV. (See “Enuresis (I)” later in the chapter for a more complete discussion of the interaction of clozapine and fluoxetine. Thus. metabolism. 1997 Greenblatt DJ. 2001 Raaska K. 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: Human cytochromes and some newer antidepressants: kinetics. when an avidly bound 1A2 substrate like caffeine was added to the regimen. et al: Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. Spigset O. deLeon J: Clozapine levels and caffeine. This led to a significant increase in the clozapine blood level. 2003 Miners JO. Br J Clin Pharmacol 44:439–446. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Laitila J. and blurry vision. Mjorndal T. Johansson I. Raitasuo V. J Clin Psychopharmacol 19(suppl):23S–35S. which caused the patient to experience increased sedation. et al: Effects of caffeine intake on the pharmacokinetics of melatonin.

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

Olanzapine is a 1A2 substrate. although it is also metabolized by 2D6 and phase II glucuronidation at the 1A4 enzyme (Callaghan et al. et al: Fluvoxamine but not sertraline inhibits the metabolism of olanzapine: evidence from a therapeutic drug monitoring service. 20 mg/day.6 µg/mL). Mihara K. so he and his psychiatrist agreed on a trial of carbamazepine (Tegretol).000 mg/day (blood level. Court MH. 1995 Weigmann H. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. 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. titrated to a dosage of 1. He was then discharged from the hospital. the psychiatrist titrated the olanzapine dosage to 40 mg/day. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. 9. Tybring G. Gerek S. 10 days later. After sharing his concerns with his psychiatrist. However. Greenblatt DJ. 2001 CONSPIRACY THEORY A 21-year-old man with bipolar I disorder was being maintained on olanzapine (Zyprexa).42 Drug–Drug Interaction Primer References Callaghan JT. 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). J Clin Psychopharmacol 15:125–131. After consulting with the hospital pharmacist. Bergstrom RF. Discussion This is an example of an inducer added to a substrate. et al: Olanzapine: pharmacokinetic and pharmacodynamic profile. Clin Pharmacol Ther 71:141–152. 2002 Niemi M. but during finals week at his college he became acutely manic and required psychiatric hospitalization. Ptak LR. 2001 von Moltke LL. he was again grandiose and paranoid. Zeisig A. He experienced improvement in his manic symptoms by day 7 while taking 1. Clin Pharmacokinet 37:177–193. Ther Drug Monit 23:410–413. Clin Pharmacol Ther 69:194–200. 1999 Christensen M.000 mg/day of carbamazepine. 1999. 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 eventually produced a remission of psychosis and no side effects. he consented to rehospitalization to formulate an appropriate defense strategy from a safe location. Neuvonen M. He had been compliant with this medication. . Backman JT.

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

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

Jerling et al. Br J Clin Pharmacol 44:439–446. 1994 . Johansson I. Engel G. 2004). Molloy M. 2004 Jerling M. Apart from this complex pharmacokinetic interaction. Ther Drug Monit 16:368–374. Svensson JO. Lindstrom L. 1988 Bottiger Y. References Arana GW. 1994). Ther Drug Monit 21:171–174. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. Miners and Birkett 1998. Drug Metab Dispos 29:1343– 1348. 1988. 3A4. and the phase II glucuronidation enzyme 1A4. et al: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Hamilton GA. Bondesson U. adverse hematological event. Rambeck et al. Spina et al. Wachsmuth H: Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine. Nemeroff CB: 2002 guide to psychotropic drug interactions.Psychiatry Case Vignettes 45 also induces the glucuronidation enzyme 1A4 (Arana et al. J Clin Psychiatry 49:448– 449. Because this medication combination carries with it an increased risk of causing a severe. Drug Metab Dispos 32:348–358. 1996. 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. there is a potential pharmacodynamic interaction of great importance and concern. Stahle L: Lamotrigine drug interactions in a TDM material. 1998. Bottiger et al. 1996. The discontinuation of the carbamazepine would be expected to yield a return to the baseline clozapine blood level in 2–3 weeks. with clozapine causing a roughly 1% incidence of agranulocytosis and carbamazepine potentially causing aplastic anemia and other blood dyscrasias. 1999 Breyer-Pfaff U. 1999. Epstein S. Wang H. Prim Psychiatry 9:28–57. Both of these agents are capable of significant bone marrow suppression. Ucar et al. Thus the addition of the carbamazepine led to an increased production of 1A2. Faucette et al. It was this set of concerns that led the pharmacist to advise discontinuation of the carbamazepine. 1997 Faucette SR. 2001 DeVane CL. This drop in the clozapine blood level caused the patient to experience a resurgence of his paranoid delusions and threatening behavior. 2002 Eiermann B. and possibly synergistic. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Parker et al. the clinician should have a compelling reason that would justify exposing the patient to such risks. These various enzymes were therefore able to more efficiently metabolize the clozapine (DeVane and Nemeroff 2002. et al: Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. 2004. The marrow suppression of these agents is certainly additive.

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

even though the olanzapine dosage had not been decreased. Clin Pharmacol Ther 71:141–152. 600 mg qhs (blood level. Greenblatt DJ. Court MH. with the discontinuation of fluvoxamine. Backman JT. 1995 Weigmann H. Had this interaction been anticipated. depressive type. et al: Fluvoxamine but not sertraline inhibits the metabolism of olanzapine: evidence from a therapeutic drug monitoring service. 2002 Niemi M. She typically experienced a seasonal variation in her mood. Neuvonen M. 516 ng/mL). and one winter she became more depressed than usual. Tybring G. . Clin Pharmacol Ther 69:194–200. 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. her psychiatrist decided to prescribe fluoxetine (Prozac). et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). 1A2 was able to resume its baseline (higher) level of metabolic activity. Therefore. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. which the psychiatrist addressed by both increasing the olanzapine dosage and adding divalproex. 1999 Christensen M.Psychiatry Case Vignettes 47 level of olanzapine than would have been expected had fluvoxamine not been present. Mihara K. This occult decrease in the olanzapine blood level unexpectedly precipitated the development of full manic symptoms. Studies in which fluvoxamine was added to olanzapine have demonstrated a more than doubling of olanzapine blood levels as a result (Weigmann et al. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. J Clin Psychopharmacol 15:125–131. Bergstrom RF. References Callaghan JT. and had the olanzapine dosage been increased to 20 mg/day with the discontinuation of the fluvoxamine. 2001 ENURESIS (I) A 38-year-old woman with schizoaffective disorder. Zeisig A. Clin Pharmacokinet 37:177–193. had maintained clinical stability with clozapine (Clozaril). leading to a decrease (probably by about 50%) in the blood level of olanzapine. After meeting with the patient and discussing treatment options. Ptak LR. with especially prominent anergia. Ther Drug Monit 23:410–413. Gerek S. 2001 von Moltke LL. et al: Olanzapine: pharmacokinetic and pharmacodynamic profile. 2001).

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

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

50 Drug–Drug Interaction Primer Christensen M.6 µg/mL. Mihara K. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. the patient mentioned that he had long noticed that the fluoxetine impaired his ability to ejaculate. Backman JT. 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 TRANSITIONS A 17-year-old with major depressive disorder was responding well to fluoxetine (Prozac). Court MH. 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. His neurologist planned to prescribe phenytoin (Dilantin). et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. . a full neurological workup. 2002 Mamiya K. When he was taken to the emergency room. 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. J Clin Psychopharmacol 15:125–131. 2001 Niemi M. He then had his first seizure. but 1 month later the patient had another seizure. he readily agreed and helped orchestrate a crossover titration from fluoxetine to mirtazapine (Remeron). 20 mg/day. 14. Yukawa E. Because the new fellow was not as conversant with P450 issues as his predecessor. and in collaboration with the fellow. 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. This crossover proceeded uneventfully. Tybring G. resulting in a hospital admission. he carefully titrated the dosage of phenytoin to 160 mg/day (blood level. Epilepsia 39:1317–1323. Shimamoto J. Clin Pharmacol Ther 71:141–152. Neuvonen M. Ther Drug Monit 23:75–77. 2001 von Moltke LL. and the eventual diagnosis of a seizure disorder (which his mother had). Two months into that treatment. and he asked if the fellow would consider switching him to another antidepressant. The neurologist appreciated the input. Greenblatt DJ. Kojima K. his phenytoin blood level was found to be only 6. et al: Phenytoin intoxication induced by fluvoxamine. 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.1 µg/mL). Clin Pharmacol Ther 69:194–200. Ieiri I. 1998 Mamiya K.

Stevens and Wrighton 1993). Because 2C9 and 2C19 were significantly inhibited. 1994 Greenblatt DJ. J Clin Psychopharmacol 14:375–376. the maintenance of this therapeutic blood level at this dosage of phenytoin was dependent on the continued presence of the 2C9/2C19 inhibitor. J Clin Psychopharmacol 19:471–472. and drug interactions. Shimamoto J. et al: Fluconazole-induced symptomatic phenytoin toxicity. metabolism. Preskorn SH: Drug-drug interaction in reverse: possible loss of phenytoin efficacy as a result of fluoxetine discontinuation. 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. and 3A4 (Greenblatt et al. 1999 Shader RI. von Moltke LL. 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. Epilepsia 39:1317–1323. 1993 . Fluoxetine (in concert with its active metabolite. Please see “Nystagmus” in Chapter 6 for a detailed discussion of the plasma protein–binding dimension of the fluoxetine-phenytoin interaction. 1998 Shad MU. von Moltke LL: Fluoxetine inhibition of phenytoin metabolism. Ann Pharmacother 28:191–195. 1999 Mamiya K. Rodriguez-Barradas MC. 1999. 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. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. 1994 Stevens JC. their ability to efficiently metabolize phenytoin was impaired. 1994. fluoxetine. Zenon GJ 3rd. Mamiya et al. Ieiri I. 1994).Psychiatry Case Vignettes 51 Discussion This is an example of reversal of inhibition. J Clin Psychopharmacol 19(suppl):23S–35S. J Pharmacol Exp Ther 266:964–971. et al: Human cytochromes and some newer antidepressants: kinetics. with the result that the phenytoin level then fell below the therapeutic range and the patient experienced another seizure (Shad and Preskorn 1999). Harmatz JS. Greenblatt DJ. Therefore. norfluoxetine) is a strong inhibitor of 2D6 and a moderate inhibitor of 2C9. Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. Once the final phenytoin dosage of 160 mg/day was generating a stable therapeutic blood level. 2C19. References Cadle RM. 1998). The first psychiatry fellow recognized that the addition of phenytoin to fluoxetine would follow the “substrate added to inhibitor” paradigm.

Mamiya et al. metabolized primarily by 2C19 and secondarily by 3A4) (MacLeod et al. in a manner similar to ticlopidine (Ticlid. disulfiram acts as an inhibitor of 2C19 as well as of 2E1. 1996). at the very least. but this is merely a possibility that cannot be excluded as yet.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. . Thus. Dresser et al. 1990. Discussion This is an example of an inhibitor added to a substrate. 500 mg/day.2 µg/mL). 1999. and a lorazepam (Ativan) taper to address the delirium tremens. and perhaps not even a likely one. see “Clots” in Chapter 4). He reported to the psychiatrist that he had found disulfiram (Antabuse) to be a helpful way to motivate him to stay “dry. and after the patient was acutely stabilized. 2000). but beyond that its enzymatic activities have not been well characterized (Emery et al. resulting in an increase in the phenytoin blood level and the accompanying delirium. he had been compliant with the disulfiram. Disulfiram has been shown to also increase blood levels of diazepam (Valium. metabolized by 3A4) (Diquet et al. and it has been shown to increase phenytoin blood levels. The patient had already had a seizure in the emergency room.” A stat phenytoin blood level was then ordered and found to be 31. A psychiatric consultant visited the patient. Because disulfiram’s inhibitory profile is otherwise not well characterized. and there was no evidence of a disulfiram–alcohol reaction. the hospitalist placed him on phenytoin (Dilantin). Ono et al. Kiorboe 1966). my belief is that. 1994. Kharasch et al.” The psychiatrist agreed to start him on disulfiram. 16. disulfiram’s presumed strong 2C19 inhibition significantly impaired the ability of this enzyme to contribute to the metabolism of phenytoin. Disulfiram is certainly a strong 2E1 inhibitor. It has also been shown to not increase levels of alprazolam (Xanax. Five days later. In view of this evidence. it may be that 2C9 inhibition could also have played a role. 1978. 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. Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. who seemed willing to make a serious attempt to curtail his drinking.9 µg/mL. However. 400 mg/day (blood level. A Breathalyzer borrowed from the emergency room confirmed that he was still “dry. Disulfiram also has no known inhibitory profile with regard to phase II glucuronidation or P-glycoprotein systems. the patient seemed intoxicated and irritable. 1999. 1998).

250 mg/day. 100 mg/day. 1994 Diquet B. Lamiable D. The psychiatrist decreased the diazepam dosage to 2 mg tid. 2000 Emery MG. Clin Pharmacokinet 38:41–57. et al: Lack of interaction between disulfiram and alprazolam in alcoholic patients. and her psychiatrist agreed to prescribe this until the sertraline (Zoloft). which caused a remission of the oversedation but some return of panic attacks. 1999 Kiorboe E: Phenytoin intoxication during treatment with Antabuse (disulfiram). 1990 Dresser GK. various stressors in her life had led to a resurgence of debilitating panic attacks. although not nearly as badly as before the diazepam was initiated. However. Epilepsia 7:246–249. J Pharmacol Exp Ther 291:213–219. 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. 1998 Ono S. Ieiri I. 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. 25 mg/ day) began to provide some relief. et al: Fluconazole-induced symptomatic phenytoin toxicity. for the past 2 years. and 3A4 activities: evidence for specificity toward P-450 2E1. and this helped her to remain abstinent from alcohol for this period. Epilepsia 39:1317–1323. et al: Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6. et al: Interaction of disulfiram with benzodiazepines. Jubert C. Gujadhur L. Ann Pharmacother 28:191–195. 1966 MacLeod SM. Xenobiotica 26:1155–1166. Thummel KE.” as compared with her prior response to this dosage of diazepam. 1978 Mamiya K. Miyazawa S. Sellers EM. Eur J Clin Pharmacol 38:157–160. 5 mg tid. Hatanaka T. Her panic attacks had responded to diazepam (Valium). Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacol Ther 24:583–589. 2D6. Hankins DC. Spence JD. The psychiatrist instructed the patient to use a pill cutter to halve the . 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. Zenon GJ 3rd. that he was also starting (initial dosage. Shimamoto J. Giles HG. 2C19 and the 3A subfamily. Rodriguez-Barradas MC. Drug Metab Dispos 27:717–723. in the past. Jubert C. However. 1999 Kharasch ED. 1996 ALCOHOL-FREE INTOXICATION A 35-year-old woman with a history of alcohol dependence and panic disorder had been taking disulfiram (Antabuse).Psychiatry Case Vignettes 53 References Cadle RM. 2C19. et al: Lack of single-dose disulfiram effects on cytochrome P-450 2C9.

1999. on the basis of clinical effect. et al: Interaction of disulfiram with benzodiazepines. metabolized primarily by 2C19 and secondarily by 3A4) (MacLeod et al. This explains why the patient became oversedated while taking a dosage of diazepam that she had previously tolerated.54 Drug–Drug Interaction Primer diazepam 2-mg tablets and then to take 3 mg tid. Gujadhur L. Giles HG. Drug Metab Dispos 27:717–723. Dresser et al. 1999 Kiorboe E: Phenytoin intoxication during treatment with Antabuse (disulfiram). to a 40% reduction of the diazepam dosage. Eur J Clin Pharmacol 38:157–160. Jubert C. Discussion This is an example of a substrate added to an inhibitor. 1996). and 3A4 activities: evidence for specificity toward P-450 2E1. 2000 Emery MG. 1990. 1996). 2000). Disulfiram has also been shown to increase blood levels of diazepam (Valium. Miyazawa S. 1978 Ono S. References Diquet B. it has been shown to not increase levels of alprazolam (Xanax. 1978. but beyond that its enzymatic activities have not been well characterized (Emery et al. 1990 Dresser GK. Lamiable D. Also. et al: Lack of interaction between disulfiram and alprazolam in alcoholic patients. and it has been shown to increase phenytoin blood levels. Xenobiotica 26:1155–1166. Spence JD. 1996 . Ono et al. Kharasch et al. Epilepsia 7:246–249. Clin Pharmacol Ther 24:583–589. Clin Pharmacokinet 38:41–57. Hankins DC. et al: Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6. 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. In view of this evidence. my belief is that. Thummel KE. The psychiatrist compensated for this effect by carefully titrating. 1966 MacLeod SM. metabolized by 3A4) (Diquet et al. Disulfiram is certainly a strong 2E1 inhibitor. disulfiram acts as an inhibitor of 2C19 as well as of 2E1. et al: Lack of single-dose disulfiram effects on cytochrome P-450 2C9. Hatanaka T. Kiorboe 1966). Sellers EM. 2C19 and the 3A subfamily. which provided optimal relief from panic without oversedation. Disulfiram also has no known inhibitory profile with regard to phase II glucuronidation or P-glycoprotein systems. J Pharmacol Exp Ther 291:213–219. 1999 Kharasch ED. This is the likely mechanism by which disulfiram elevates the blood level of diazepam. 1999. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Diazepam is a substrate primarily of 2C19 and secondarily of 3A4 (Ono et al. 2D6. at the very least. Jubert C. 2C19.

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

there was an increase in the blood level of diazepam. 2001. the addition of the omeprazole significantly impaired the ability of 2C19 to contribute to the metabolism of diazepam. She shared this information with her psychiatrist. who was puzzled but pleasantly so. 1994). Predictably. Because 3A4 was not able to entirely compensate for this 2C19 inhibition. and her coworkers supported this perception. She was more efficient and unflustered during a tax season than she could ever recall. 1995). She did not require any extra doses of diazepam for the entire tax season. Within 5 days. for this problem. 20 mg/day. He prescribed omeprazole (Prilosec). she experienced an unusual absence of inner turmoil during what was usually a stressful period. Clin Pharmacol Ther 58:62–72. 1996). which prompted a visit to her internist. but it appears that this patient had been chronically and mildly undertreated. and omeprazole is a strong inhibitor of 2C19 as well as an inducer of 1A2 (Furuta et al. For his part.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). she experienced increasing indigestion and heartburn pain. 1995 . she always became more nervous around March because of the crush of yearly tax submissions. he had been surprised that he had not received any extra phone calls from the patient for the past month. One March. Nousbaum et al. Tateishi T. Diazepam is a substrate primarily of 2C19 and secondarily of 3A4 (Ono et al. References Caraco Y. She continued to enjoy a sense of calm that persisted beyond the tax season. 5 mg tid. Studies have demonstrated that the addition of omeprazole to diazepam will typically increase blood levels of diazepam by roughly 40% (Caraco et al. but he ascribed that to character development and the patient’s finding more mature coping mechanisms with age. Her psychiatrist would supply her with one or two as-needed doses of diazepam per week to offset this period of heightened stress. and her use of diazepam had remained stable over the years. such that the increase seems to have produced an as yet unrecognized clinical benefit for this patient. This increase in the diazepam blood level might have ordinarily produced unwanted sedation or cognitive slowing. Discussion This is an example of an inhibitor added to a substrate. Wood AJ: Interethnic difference in omeprazole’s inhibition of diazepam metabolism. Thus.

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

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

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

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

900 mg/day (blood level.7 µg/mL. 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. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. et al: Inhibition of diazepam metabolism by fluvoxamine: a pharmacokinetic study in normal volunteers. increasing libido. Greenblatt DJ. the patient tolerated this lower dose of diazepam without difficulty. because he had been taking a different anticonvulsant before he was switched to phenytoin. 1995 ANTIDEPRESSANT WITHDRAWAL SEIZURE A 22-year-old man with bipolar I disorder and a seizure disorder was being maintained on lithium.75 mEq/L). The patient began to display emerging manic symptoms (decreasing need for sleep. 2C19 and the 3A subfamily. the patient experienced a seizure and his phenytoin blood level was found to be only 4.4 µg/mL). J Clin Psychopharmacol 15:125–131. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride.Psychiatry Case Vignettes 61 become sedated. He had been seizure free for the previous 2 years. Miyazawa S. Mihara K. Backman JT. 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. 150 mg/day. increased rate of speech and distractibility). Cipolla G. Tybring G. and phenytoin (Dilantin). 2001 Ono S. Clin Pharmacol Ther 56:471–476. in part. Gatti G. 12. 1996 Perucca E. 0. Clin Pharmacol Ther 71:141–152. References Christensen M. . 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. et al: Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6. 1994 von Moltke LL. Neuvonen M. Hatanaka T. Xenobiotica 26:1155–1166. fluvoxamine (Luvox). Ten days later. to some anxiolytic contribution (albeit not through direct γ-aminobutyric acid agonism) from the fluvoxamine. 300 mg/day (blood level. Her positive response was possibly due. The phenytoin was the most recent addition to this regimen. 2002 Niemi M. Clin Pharmacol Ther 69:194–200. so his psychiatrist discontinued the fluvoxamine.

Backman JT. This caused the patient to have his first seizure in 2 years. 20 mg qhs. 1995 LESS IS MORE A 32-year-old man with schizoaffective disorder. bipolar type. Ther Drug Monit 23:75–77. Tybring G. Zenon GJ 3rd. 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: Fluconazole-induced symptomatic phenytoin toxicity. Mihara K. Clin Pharmacol Ther 69:194–200. 2002. His inpatient psychiatrist decided that he should begin receiving a deca- . von Moltke et al. Greenblatt DJ. 2C9 and 2C19 resumed their higher baseline levels of activity. Mamiya et al. Niemi et al. Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. resulting in more efficient metabolism of the phenytoin and a subsequent decrease in the phenytoin blood level to the subtherapeutic range. References Cadle RM. et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. 1998 Mamiya K. Ann Pharmacother 28:191–195. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. had been noncompliant with his olanzapine (Zyprexa). et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). 1994 Christensen M.62 Drug–Drug Interaction Primer Discussion This is an example of reversal of inhibition. Yukawa E. Thus. 2001. Rodriguez-Barradas MC. et al: Phenytoin intoxication induced by fluvoxamine. 1994. 2001). 1995). When the fluvoxamine was discontinued. which produced a blood level of 10. 1998). Epilepsia 39:1317–1323. Ieiri I. Clin Pharmacol Ther 71:141–152. Kojima K. 2002 Mamiya K. Neuvonen M. This problem was eventually addressed by the psychiatrist’s increasing the phenytoin dosage to 600 mg/day. 2C9. Shimamoto J. Court MH.8 µg/mL. and fluvoxamine is a strong inhibitor of 1A2. 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. 2001 Niemi M. J Clin Psychopharmacol 15:125–131. 2001 von Moltke LL. and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. which led to a psychotic decompensation with manic features and subsequent hospitalization.

however.Psychiatry Case Vignettes 63 noate preparation of haloperidol (Haldol) to address his recurrent medication noncompliance. 1988. At about the same time. Haloperidol is metabolized by 3A4. 2D6. 1998. When the carbamazepine was discontinued. 1A2. 2004. the resulting blood level was now sufficient to generate both an antipsychotic response . 2C9. Miners and Birkett 1998. and 3A4. he instead chose to decrease the haloperidol back to 10 mg/day. the patient’s psychotic symptoms had almost completely remitted. Kudo and Ishizaki 1999). and possibly pertinent phase II glucuronidation enzymes that were available to metabolize the haloperidol. 1A2. 2003). and metabolically available levels of 3A4. Rambeck et al. but his paranoid delusions and auditory hallucinations persisted with unabated strength. 1996. Bottiger et al.100 cells/µL. 9. with the patient taking the same dosage of haloperidol. The haloperidol was further increased to 20 mg/day in an effort to treat these psychotic symptoms. 1996. Lucas et al. the patient was slightly calmer. the “extra” 3A4. One week later. as had all of his side effects. specifically including 1A2. 1999. 10 mg/day. because his current presentation was characterized by more violence than usual. In this case. 2001.100 cells/µL to 2. The carbamazepine was abruptly discontinued. 1A2. the patient’s psychotic symptoms continued to improve. The carbamazepine increased the amounts of 3A4. This led to a decrease in the metabolism of haloperidol and a subsequent increase in the haloperidol blood level. 2004). but after a conversation with the hospital pharmacist. It also induces uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 (Arana et al. but the psychiatrist discovered that the patient’s white blood count had dropped from 6. leading to a haloperidol blood level that was potentially subtherapeutic despite the use of fairly high doses (Hesslinger et al. and phase II glucuronidation (Desai et al. Also. Discussion This is an example of reversal of induction.7 µg/mL). and carbamazepine is an inducer of multiple P450 enzymes. Ucar et al. including the akathisia. titrating to a dosage of 800 mg/day (blood level. Faucette et al. he began to experience cogwheel rigidity and mild akathisia. and glucuronidation enzymes returned to their (lower) pre-carbamazepine baselines. 1A2. and possibly pertinent glucuronidation enzymes that were produced by carbamazepine’s induction died off. 1998. Yasui-Furukori et al. Ten days later. After 2 weeks at this dosage of carbamazepine. Parker et al. 2B6. One week later. The psychiatrist added benztropine (Cogentin) for the cogwheeling and strongly considered adding propranolol (Inderal) for the akathisia. the psychiatrist added carbamazepine (Tegretol). he was started on oral haloperidol. Spina et al. the psychotic symptoms began to diminish. In preparation for this. 1999.

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

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

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

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

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

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

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

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

Venlafaxine. the considerable amount of norfluoxetine that was present when venlafax- . The venlafaxine was discontinued. with little clinical benefit. is an equally potent serotonin reuptake inhibitor. Thus. 1993 PREMATURE CROSSOVER A 23-year-old woman with a history of melancholic major depression was given fluoxetine (Prozac).R. Scordo MG. Within another 3 days. However. 2002 Stevens JC.72 Drug–Drug Interaction Primer Spina E. 2001). A likely contributor to this serotonin syndrome was the pharmacokinetic interaction between fluoxetine and venlafaxine. and she was admitted to the medical floor of a nearby hospital. et al: Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction. but she waited another 4 weeks before doing so (J. Venlafaxine is predominantly a substrate of 2D6 (Wyeth Laboratories 2002). and fever. May 2002). Thus. norfluoxetine. 150 mg/day. where she received supportive treatment with antipyretics and lorazepam (Ativan). J Clin Psychopharmacol 22:419–423. Her psychiatrist decided to embark on a trial of venlafaxine (Effexor). also functions as a potent serotonin reuptake inhibitor. but its average half-life is 17 days (Brunswick et al. which was titrated to a dosage of 60 mg/day. and fluoxetine/ norfluoxetine is a potent 2D6 inhibitor (Stevens and Wrighton 1993). fluoxetine’s major metabolite. Three days after abruptly discontinuing the fluoxetine. and especially norfluoxetine’s. Discussion This is a combined example of a substrate added to an inhibitor and excessive pharmacodynamic synergy. 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. personal communication. She was discharged without complications 2 days later. J Pharmacol Exp Ther 266:964– 971. Fluoxetine is a potent selective serotonin reuptake inhibitor with an average half-life of 1–3 days (Eli Lilly/Dista Pharmaceuticals 2001). The end result was a mild to moderate central serotonin syndrome leading to an avoidable hospitalization. still considerable serotonin reuptake inhibitor activity combined with that of venlafaxine. at 150 mg/day. the patient was started on venlafaxine XR. diarrhea. Avenoso A. the patient experienced disturbing myoclonus along with flushing. She did eventually try venlafaxine again. Oesterheld. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450.

Eli Lilly/Dista Pharmaceuticals. 200 mg/day (blood level. which qualified as a long period of stability for this patient. the patient’s resulting symp- . Thus.1 µg/mL. the patient developed increasing lethargy and confusion. the psychiatrist discontinued the sertraline and started the patient on citalopram (Celexa). IN. 1999). et al: Fluoxetine and norfluoxetine plasma levels after discontinuing fluoxetine therapy. J Clin Psychopharmacol 21:616– 618. for the past 18 months. Fawcett J. so her psychiatrist decided to introduce sertraline (Zoloft) at a low dosage (25 mg/day) into her regimen. seemingly unique among the selective serotonin reuptake inhibitors. which was found to be 5. Because the final lamotrigine blood level was not terribly high (5. Wyeth Laboratories. 2001 Eli Lilly/Dista Pharmaceuticals: Prozac (package insert). Amsterdam JD. specifically by the uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 enzyme (Hiller et al. When she reported this to her psychiatrist. leading to a greater-than-expected blood level of venlafaxine and thereby increasing the likelihood of an adverse event such as a serotonin syndrome.1 µg/mL). After consulting with the affiliated hospital’s pharmacist. Discussion This is an example of an inhibitor added to a substrate. and insomnia began to develop. Sertraline. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. is an inhibitor of UGT1A4 (Kaufman and Gerner 1998). the addition of sertraline (and at a low dosage at that) significantly impaired the ability of UGT1A4 to metabolize the lamotrigine. Over the next several days. References Brunswick DJ.Psychiatry Case Vignettes 73 ine reached steady state was still able to strongly inhibit 2D6. Lamotrigine is metabolized primarily through phase II glucuronidation. Some persistent dysphoria. anhedonia. he ordered another lamotrigine blood level. 2001 Stevens JC. This led to a sharp increase in the blood level of lamotrigine. J Pharmacol Exp Ther 266:964–971. 2. 2002 A LITTLE GOES A LONG WAY A 36-year-old woman with bipolar I disorder had been stably maintained on lamotrigine (Lamictal). with no further difficulties of this nature.5 µg/mL). Philadelphia. a doubling in this case (Kaufman and Gerner 1998). PA. Indianapolis. 1993 Wyeth Laboratories: Effexor (package insert).

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

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

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

In this case. 1998 RASH DECISION (I) A 30-year-old woman with a history of bipolar I disorder had been stably maintained on lamotrigine (Lamictal). 8th Edition. Grossly speaking. The psychiatrist instructed the patient to go to the emergency room to obtain a lithium blood level. usually by roughly 25%–40% (Crabtree et al. dysarthria. ataxia. Peabody CA: Clinical relevance of drug interactions with lithium. Clin Pharmacokinet 29:172–191. von Riotte AB. which was 1. she was recently hospitalized because of a breakthrough manic episode. References Batlle DC. Hydrochlorothiazide causes increased sodium excretion at the distal convoluted tubule of the nephron. 1995).Psychiatry Case Vignettes 77 anticipated paradoxical effect of decreasing the patient’s urine production. 1991 Finley PR.4 mEq/L. 0. MD. the resulting blood level produced a state of mild lithium toxicity. N Engl J Med 312:408–414. Baltimore. Johnson CD. which accomplishes the same decrease in urine production but generally without significant changes in lithium or potassium levels (Batlle et al. the kidney tries to compensate for this effect by retaining sodium at other portions of the nephron. 250 mg/day. and sedation. and 1. A better choice for decreasing urine output in lithium-induced diabetes insipidus would have been amiloride (Midamor). 1995 Kaplan H. Am J Psychiatry 148:1060–1063.9 mEq/L) of lithium. However. et al: Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. Finley et al.9 mEq/L). because the baseline lithium level was relatively high (0. Gaviria M. over the next 3 days he experienced increasing tremor. 1991. Warner MD. Williams and Wilkins. This retention of lithium then produces an increase in the lithium blood level. 1985).200 mg/day (blood level. Sadock B: Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/ Clinical Psychiatry. Because lithium and sodium are both monovalent cations. 1985 Crabtree BL. Because of her aversion to the concept of antipsychotic medication. the kidney confuses the two ions and thus acutely decreases its clearance of lithium as well (Kaplan and Sadock 1998). she declined the offer of an ad- . et al: Comparison of the effects of hydrochlorothiazide and furosemide on lithium disposition. Mack JE. Discussion This is an example of lithium toxicity caused by a sodium-depleting agent.

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

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

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

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

First. and ammonia level. divalproex sodium (Depakote). 50 mg/day. clonazepam (Klonopin). 9. carbamazepine. Bottiger et al. loxapine (Loxitane). 120 µg/mL).0 mEq/L). 8. and the staff observed that his gait had become unsteady. many laboratory studies were obtained.2 µg/mL.500 mg/day (blood level. Spina et al. 1999. alanine aminotransferase. involving multiple P450 enzymes and phase II glucuronidation. 2C9.” Over a 2-week period. 2004. 1. the patient was increasingly lethargic and irritable. It also induces uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 (Arana et al. 65 µmol/L. but his bipolar illness had not responded to the following regimen: lithium. 1996. 1 mg bid. 1988. Discussion This is a mixed example of an inducer (carbamazepine) added to a substrate (divalproex) and a substrate (carbamazepine) added to an inhibitor (divalproex). The next morning. Significant test results included the following levels: divalproex. specifically including 1A2. Carbamazepine is an inducer of multiple P450 enzymes. the carbamazepine was titrated to 800 mg/day (blood level. Ther Drug Monit 21:175–181. Faucette et al. rapid-cycling bipolar I disorder and a comorbid seizure disorder had been consistently seizure free.82 Drug–Drug Interaction Primer May TW. 2 mg bid. 1998. His psychiatrist decided to add carbamazepine and thus go to “triple therapy. 48 µg/mL. 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. After 2 weeks at this dosage of carbamazepine. he had his first grand mal seizure in 2 years. and benztropine. Lucas et al. 1998. 2B6. and 3A4. 2004). the most likely means by which carbamazepine influences the metabolism of divalproex is through the increased production . Miners and Birkett 1998.7 µg/mL). Later that day. Jurgens U: Influence of oxcarbazepine and methsuximide on lamotrigine concentrations in epileptic patients with and without valproic acid comedication: results of a retrospective study. He reported the emergence of auditory hallucinations and seemed preoccupied with the observation cameras on the unit. 82 IU/L (previously within normal limits). Of these possible points of interaction. Rambeck B. Parker et al. 1. 1996. 1999 DISEQUILIBRIUM A hospitalized 28-year-old man with treatment-resistant. 1.050 mg/day (blood level. Ucar et al. Rambeck et al. the metabolism of divalproex is exceedingly complex.

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

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

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

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

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

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

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

With a binding coefficient of 0. his agitation. 2003).34 (Otsuka Pharmaceutical 2002). As a 25%–30% partial dopamine agonist at the D2 receptor. aripiprazole is unique even among atypicals (Burris et al. 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.90 Drug–Drug Interaction Primer creased to 15 mg/day. as this case and others like it demonstrate. it binds twice as avidly to the D2 receptor as even a robust binder like haloperidol (binding coefficient. Fortunately. aggression. and psychotic symptoms began to remit. decompensation during aripiprazole crossover titrations does not occur most of the time (Casey et al. Because this would occur before aripiprazole had been administered for a long enough period to exert its own antipsychotic mechanism of action. 2002). such as haloperidol. 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. Typical antipsychotics. However. the aripiprazole was discontinued. However. this situation creates a window of vulnerability to decompensation that is difficult to avoid. Another unique feature of aripiprazole is the extreme avidity with which it binds to the D2 receptor. 0. cross-titrating to aripiprazole makes it very difficult to provide this protection against avoidable decompensation. 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 . Three days after stopping the aripiprazole. generally exert their primary antipsychotic effect through antagonism of the dopamine D2 receptor. However. even if the original agent is maintained at its baseline dosage. eventually requiring hospitalization. 1996). he continued to decompensate over the next several days.7) at equimolar concentrations (Bymaster et al. It is considered a prudent principle of crossover titrations that the more gradually they proceed. the less likely that decompensation will occur due to premature taper of the original agent. Atypical antipsychotics are thought to employ a broader range of potential antipsychotic mechanisms. Once he was hospitalized. 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. He eventually reachieved his more functional baseline 3 weeks after the aripiprazole was discontinued. The extreme avidity of this drug for the D2 receptor effectively and significantly displaces the original drug from the D2 receptor.

the patient had a friend who recently experienced acute renal failure due to some unrelated cause. Neuropsychopharmacology 14(2):87–96. 2002 POLYURIA A 46-year-old male with a history of bipolar I disorder had been stably maintained on a combination of lithium.8 mEq/L) and venlafaxine (Effexor XR). whereupon lithium was added to his regimen. 2002 Bymaster FP. Xu C. Saha AR. Calligaro DO.5 mg/day. About 10 years earlier. his venlafaxine was decreased to 37. The patient and his psychiatrist collaborated on a plan to transition him to monotherapy with valproate. et al: Aripiprazole. is a highaffinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302(1):381–389. Although it was not firmly quantified. 250 mg bid. Falcone JF.Psychiatry Case Vignettes 91 that support. 75 mg/day. likely due to dehydration. Although the psychiatrist did not understand how the discontinuation of the venlafaxine might have led to the patient’s polyuria.” Over the next several days. a novel antipsychotic. Although the patient did not experience any typical serotonin withdrawal symptoms. 1996 Casey DE. September 2003). he did report marked and troubling polyuria. He had never received lithium without the venlafaxine. was added to his regimen. After 1 week at this decreased dosage. Two weeks later. Molski TF. which he tolerated without difficulty. Psychopharmacology 166(4):391–399. personal communication. the chronology of events implicated this as the most . divalproex sodium. and this was also well tolerated. 0. the patient experienced disruption of his sleep and dizziness. the patient had been diagnosed with major depressive disorder and was being treated with venlafaxine. the venlafaxine was stopped altogether. Initially. he reported that he was urinating “constantly. et al: Radioreceptor binding profile of the atypical antipsychotic olanzapine. 2003 Otsuka Pharmaceutical: Abilify (package insert). his urinalyses and serum creatinine values had been consistently normal. Zuzarte. et al: Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study. Japan. Tokyo. or discontinuation of the crossover titration can be instituted as soon as possible (E. Carson WH. However. Otsuka Pharmaceutical. the patient had his first manic episode. References Burris KD. and this led him to become more concerned about possible nephrotoxicity associated with long-term lithium treatment. 900 mg/day (blood level. adjunctive treatment measures. Since then. After several months of taking the venlafaxine.

92 Drug–Drug Interaction Primer likely causative factor. Neth J Med 50:243–245. producing frank diabetes insipidus. 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. personal communication. Weggery S. 1996 Masood GR. Mittmann N. Ciroldi M. Karki SD. leading to the development of marked polyuria. Kidney Int 67:291–294. 1997). Venlafaxine is also a potent inhibitor of serotonin reuptake. 1998 Meynaar IA. et al: Syndrome of inappropriate ADH secretion attributed to the serotonin re-uptake inhibitors. 2005 . 2005). venlafaxine and paroxetine. and there are case reports of venlafaxine producing SIADH (Izzedine et al. 2002. Patterson WR: Hyponatremia with venlafaxine. 2002 Liu BA. Bedford JJ. et al: Lithium-induced reduction in urinary concentrating ability and urinary aquaporin 2 (AQP2) excretion in healthy volunteers. CMAJ 155:519–527. Knowles SR. Nephron 92:944–946. Peeters AJ. 1998. namely a syndrome of inappropriate antidiuretic hormone production (SIADH). 1996). Ann Pharmacotherapy 32:49–51. August 2006). 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. Masood et al. Launay-Vacher V. when the venlafaxine was discontinued. References Izzedine H. this effect can be quite troublesome. Thus. Mulder AH. However. lithium’s propensity to increase urine production was no longer inhibited. However. 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. Discussion This is an example of offsetting drug side effects. The psychiatrist therefore restarted the venlafaxine. and within 3 days the patient’s polyuria had almost completely resolved (N. 1997 Walker RJ. Meynaar et al. In some individuals. and this effect seems to result from increased serotonin neurotransmission (Liu et al. 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. it seems that he was fortunate that venlafaxine produced a counteracting effect that enabled him to tolerate lithium treatment. for this patient. SIADH occasionally occurs in individuals (most often in the elderly) who take a selective serotonin reuptake inhibitor. et al: Fanconi and inappropriate secretion of antidiuretic hormone syndromes secondary to venlafaxine therapy. Sandson.

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

” with powers that exceeded even the president’s. October 2004). She was stabilized in the emergency room and blood was drawn for laboratory studies to determine the cause of her new symptoms. Gibaldi M. 1987 Kunze KL. personal communication. This relationship progressed to the point that she visited her internist in order to start taking an oral contraceptive. the patient enjoyed a remarkable recovery of her functioning. Trager WF. She had previously failed trials of risperidone (Risperdal). and she had started dating a young man she had met while working as a volunteer in the hospital gift shop. 1999 Schrenk D. Within 1 week of beginning the contraceptive. Lewis GM: Increase in international normalized ratio after smoking cessation in a patient receiving warfarin. Chirality 3:24–29. Pharmacotherapy 20:1464–1468. et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. Brockmeier D. Pharmacotherapy 25:1656–1659. Three days later. 1998 Zevin S. Mol Diagn 4:365–379. et al: The mechanism of the warfarin–rifampin drug interaction. . Gibaldi M. 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. 2005 Heimark LD. 2000 Linder MW. and dizziness. who was able to see her immediately. Clin Pharmacokinet 36:425–438.94 Drug–Drug Interaction Primer References Evans M. olanzapine (Zyprexa). Eddy AC. et al: Metabolic enantiomeric interactions: the inhibition of human (S)-warfarin-7-hydroxylase by (R)-warfarin. and haloperidol (Haldol). Clin Pharmacol Ther 42:388–394. 448 µg/mL). She was planning to reenter college on a limited basis. and the laboratory reported that her clozapine level had increased to 1. Her oral contraceptive was also discontinued. Valdes R Jr: Pharmacogenetics in the practice of laboratory medicine. anergy. Eur J Clin Pharmacol 53:361–367. 1991 Lehmann DE: Enzymatic shunting: resolving the acetaminophen-warfarin controversy. Eckermann. Morike K.281 ng/mL (G. eventually titrating to a dosage of 400 mg/day (blood level. She was planting herself in the middle of busy intersections and proclaiming that she was the “Grand Tekulek. The psychiatrist determined that she was orthostatic and arranged for her to be evaluated in the emergency room. Her psychiatrist decided to initiate a trial of clozapine (Clozaril). Over the next 6 months. Benowitz NL: Drug interactions with tobacco smoking: an update. the patient was experienced marked drowsiness. she was feeling much better. She reported this sequence of events to her psychiatrist.

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

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

Ther Drug Monit 21:293–296. 1998.8 µg/mL). Brockmeier D. He managed to largely suppress this during the examination. Jann MW: Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. he was smoking in the waiting room when his psychiatrist came out of his office to invite him inside. whose illness course had been characterized by infrequent manic episodes and even fewer depressions. is a significant 1A2 inducer (Schrenk et al. 1999 THE ROAD TO HELL IS PAVED WITH INDICATIONS A 37-year-old male with bipolar I disorder. References Desai HD. resulting in a decrease in the blood level of haloperidol (Shimoda et al. Clin Pharmacokinet 37:435–456. Ishizaki T: Pharmacokinetics of haloperidol: an update. had been stably maintained on carbamazepine (Tegretol). After the death of his sister. et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. 2D6. 1999 Schrenk D. 2001 Kudo S. via cigarette smoking. Someya T. The psychiatrist thus learned that the patient had begun smoking. Kudo and Ishizaki 1999). 800 mg/day (blood level. Benowitz NL: Drug interactions with tobacco smoking: an update. 2001. Morike K. he significantly increased the amount of 1A2 that was available to metabolize the haloperidol. 10. Discussion This is an example of an inducer added to a substrate. 1999) even though the dosage had not been decreased. endorsing . a problem he had not encountered for several years. This led to a resurgence of verbal tics. Haloperidol is metabolized by 3A4. and phase II glucuronidation (Desai et al. Clin Pharmacokinet 36:425–438. He immediately made an appointment with his psychiatrist. and when he learned the reason for this urgent appointment. 1A2. 1999 Zevin S. 1998 Shimoda K. Tobacco use. Seabolt J. et al: Lower plasma levels of haloperidol in smoking than in nonsmoking schizophrenic patients. he became acutely depressed. Morita S. CNS Drugs 15:469–494. Due to his anxiety. He had not tolerated previous trials of lithium and valproate. he was able to explain to him why his symptoms had returned. Eur J Clin Pharmacol 53:361–367. Zevin and Benowitz 1999).Psychiatry Case Vignettes 97 pectedly found himself voicing a few obscenities. When the patient began smoking.

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

1996b Weiss J. SSRI antidepressants. 1996 Staines AG. et al: Psychotropic interactions with warfarin. 2001 Sayal KS.3 µg/mL) as a successful treatment for a complex partial seizure disorder. Fedrowitz M. Drug Metab Dispos 30:1170–1179. He began to experience dysphoria. Harmatz JS. Duncan-McConnell DA. J Pharmacol Exp Ther 305:197–204. 1996a von Moltke LL. 2004 von Moltke LL. His obsessional. J Pharmacol Exp Ther 311:1131–1137. McConnell HW. Dormann SM. rapidly titrated to 200 mg/day. 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. Vakkalagadda GR. I: characterization of human cytochromes P450 responsible for the formation of 2. had responded well to fluvoxamine. 1.g. et al: Inhibition of P-glycoprotein by newer antidepressants. et al: Phenacetin O-deethylation by human liver microsomes in vitro: inhibition by chemical probes. and weight loss. Pisani F. decreased concentration and energy. Greenblatt DJ.Psychiatry Case Vignettes 99 Pearce RE. Clin Pharmacokinet 31:198–214. His older brother. SPEAK NO EVIL A 25-year-old male medical student had been taking carbamazepine (Tegretol). family obligations).. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Psychopharmacology (Berl) 128:398–407. health. The patient made an appointment with his internist. et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. In the middle of his third year of medical school. Martin-Facklam M. Burchell B: N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. 2003 SEE NO EVIL. the patient noted increasing leth- . 2002 Potschka H. Duan SX. Coughtrie MW. 9. he was having difficulty translating his success in the basic sciences to his clinical work. who started him on fluvoxamine (Luvox). Leeder JS: Pathways of carbamazepine bioactivation in vitro. HEAR NO EVIL. 2000 Spina E. who had encountered similar issues and difficulties.” His perfectionism drove him to spend even more time at work.and 3-hydroxylated metabolites. Over the next several days. leading him to further compromise already neglected aspects of his outside life (e. 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. Neuroreport 12:3557–3560. J Pharmacol Exp Ther 276:370–379.000 mg/day (blood level. nefazodone and venlafaxine. poor sleep. friendships. Greenblatt DJ. Acta Psychiatr Scand 102:250–255.

2001) and fluvoxamine is an inhibitor of this transporter (Weiss et al. Acta Psychiatr Scand 84:583–584. Discussion This is an example of an inhibitor added to a substrate. 2003). Consequences for the carbamazepine plasma level]. 2002 Cottencin O. Fritze et al. 1A2. who instructed him to report to the hospital emergency room. Mihara K. where it would then be excreted rather than absorbed. Consequently. 1995 Fritze J. he did not hear his alarm and overslept by 4 hours. Sayal et al. 2B6. 1A2. Carbamazepine is a substrate of the P-glycoprotein transporter (Potschka et al. Thevenon-Gignac C. fluvoxamine also raised carbamazepine levels by impairing the ability of P-glycoprotein to extrude carbamazepine from enterocytes back into the gut lumen. Regnaut N. 2002. It is also likely that alterations in the functioning of the P-glycoprotein transporter contributed to this interaction. 1995. 2004).4 µg/mL. and 2C9. 2E1. One week after starting the fluvoxamine. thus increasing net absorption and decreasing net excretion of carbamazepine. Carbamazepine is primarily a 3A4 substrate. Hemeryck and Belpaire 2002. Encephale 21:141–145. His vision had become so blurry he was having difficulty reading. His speech was slurred and he felt “drugged. and 2C9 to efficiently metabolize the carbamazepine. Spina et al. Belpaire FM: Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19).100 Drug–Drug Interaction Primer argy and occasional nausea. and phase II enzymes (uridine 5′-diphosphate glucuronosyltransferase 2B7) making minor contributions to carbamazepine’s metabolism (Pearce et al. 2002. et al: [Carbamazepine-fluvoxamine interaction. with 1A2. Fluvoxamine is a potent inhibitor of 1A2 and a mild to moderate inhibitor of 3A4 and 2C9 (Christensen et al. Staines et al. Unsorg B. where his carbamazepine level had risen to 18. the blood level of carbamazepine rose even though the carbamazepine dosage had not been increased (Cottencin et al.” He contacted his internist. In addition to inhibiting 3A4. 2002 . The addition of fluvoxamine led to a significant impairment in the ability of 3A4. References Christensen M. 1996. 1991). 2C8/9. 2000). Clin Pharmacol Ther 71:141–152. 1991 Hemeryck A. Tybring G. Curr Drug Metab 3:13–37. Lanczik M: Interaction between carbamazepine and fluvoxamine.

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

References Gibson GG. Acute administration of benzodiazepines for acute prophylaxis of delirium tremens is the preferred manner of dealing with alcohol withdrawal seizures. The patient was very resistant to trying any antipsychotic agents. Within 2 weeks. His psychiatrist opted to add carbamazepine (Tegretol). 0. 2D6. and 3A4. Eur J Clin Pharmacol 58:423–429. Previous attempts to decrease his sertraline had resulted in a recurrence of OCD symptoms. Clin Pharmacokinet 38:461–474. van den Heuvel MW. the addition of phenytoin results in a 46% decrease in mirtazapine blood levels (Spaans et al. 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).000 mg/day (blood level. the patient’s mania did respond favorably. but he was rapidly becoming more preoccupied by cleanliness ob- . if it is used. titrating to 1. Sitsen JM. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. et al: Concomitant use of mirtazapine and phenytoin: a drug-drug interaction study in healthy male subjects. 2000 Timmer CJ. el-Sankary W. 10. Toxicology 181–182:199–202. 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. Delbressine LP: Clinical pharmacokinetics of mirtazapine. Drug Metab Dispos 28:1168–1175. et al: Metabolism of the antidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2. even though the dosage had not been decreased. this led to a significant increase in the amount of 3A4 that was available to metabolize the mirtazapine. then phenytoin should be tapered and discontinued after acute alcohol withdrawal has subsided. Shader RI. Drug Metab Dispos 31:533–539. Although there is debate about the utility of phenytoin if an alcohol withdrawal–induced seizure actually occurs. 600 mg bid (blood level. resulting in a decrease in the blood level of mirtazapine and loss of antidepressant efficacy. After getting only 2 hours of sleep for two nights in a row to complete a work project. 2002 Stormer E. 2002 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products.9 mEq/mL) and sertraline (Zoloft). Schnabel PG. One study indicates that on average.102 Drug–Drug Interaction Primer phenytoin was added to the regimen.1 µg/mL). 2003 Spaans E. von Moltke LL. 2002). he experienced a nonpsychotic manic episode leading to a voluntary hospital admission. 200 mg/day.

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

2004 A PLETHORA OF PILLS A 37-year-old male with schizophrenia had failed trials of haloperidol. this dosage produced a blood level of 458 ng/mL. Eiermann et al. Eur J Clin Pharmacol 59:879– 882. the patient’s seizures had completely remitted. quetiapine. 1999. A negative work-up suggested that the cause for these seizures was the clozapine. 1998. 1997.8 µg/mL). with 2D6. Another clozapine level drawn 5 days after hospitalization. Gibson et al. and the patient symptoms greatly decreased over the ensuing month. 2C19. Luurila H. as well as seeming more distracted. Within 1 month. and UGT1A4 that were available to metabolize the clozapine. Discussion This is an example of an inducer added to a substrate. and withdrawn. When he started stealing and destroying the underwear of his roommates in his group home. Chetty et al. At steady state. When phenytoin was added to the clozapine. and he was rehospitalized. 400 mg/day (blood level. the decision was made to keep the patient on clozapine. Unfortunately. a neurologist was consulted and phenytoin (Dilantin). and uridine 5′diphosphate glucuronosyltransferase (UGT) 1A3 and 1A4 playing only minor metabolic roles (Breyer-Pfaff and Wachsmuth 2001. However. 500 ng/mL).104 Drug–Drug Interaction Primer Ucar M. when compliance could be assured. Clozapine’s metabolism occurs primarily at 1A2. and UGT1A4 (Bottiger et al. 2002. His clozapine level at that time had fallen to 119 ng/mL. Olesen and Linnet 2001). the patient developed new-onset seizures. 3A4. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. After consulting with the hospital pharmacist. The enzymes 3A4 and 2C19 are also significant contributors. 800 mg/day (blood level. Neuvonen M. this led to a significant increase in the amount of 2C9. olanzapine. and aripiprazole before finally responding to clozapine. resulting in a decrease in the blood level of clozapine and loss of antipsychotic efficacy even though the dosage had not been decreased. was added to his regimen. after 6 months at this dosage. the patient again became preoccupied with looking at himself in the mirror for many hours each day. 2C9. Raucy 2003). 15. 2C19. the psychiatrist titrated the patient’s clozapine to a dose of 3. However. but because no other antipsychotic agents had proven helpful.000 mg/day. 3A4. guarded. Phenytoin is an inducer of multiple enzymes. specifically including 2C9. was still only 127 ng/mL. It is estimated that adding phenytoin to clozapine results in a roughly 65%–85% . this confirmed that he had decompensated to his pre-clozapine baseline.

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

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

Accordingly. He reported these symptoms to his family physician. who evaluated the patient. 107 . and the result was 623 ng/mL. One week after reaching this dosage. his symptoms fully remitted. His father had died in his mid-40s from a myocardial infarction. the physician started the patient on bupropion (Zyban.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). 200 mg/day. A week after the desipramine was stopped. The patient’s electrocardiogram showed a sinus tachycardia of 132 beats per minute and QRS interval widening to a duration of 160 msec. with a stable blood level of around 150 ng/mL. The patient was admitted to a telemetry unit. where a desipramine level was drawn before the drug was discontinued. titrating to a dosage of 150 mg bid. As part of this program. The patient was also a two-pack-per-day smoker. this patient’s family physician strongly advised the patient to participate in an aggressive smoking cessation program. the patient began to experience frequent palpitations and accompanying light-headedness. in this application).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This resulted in a . The addition of nefazodone significantly impaired the ability of 3A4 to metabolize the simvastatin. Ruths. Barry M. and his urine output declined sharply. titrating the drug to a dosage of 600 mg/day over the course of 3 weeks. 1996 STYMIED BY STATINS (II) A 57-year-old man with hypercholesterolemia was taking simvastatin (Zocor) to address this. he was found to have a creatine phosphokinase level above 2. Flockhart DA. anergy. Clin Pharmacokinet 38:41–57. even though the dosage had not changed. norfluoxetine. poor appetite. and fever. et al: Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine. J Clin Psychopharmacol 15:387–398. he prescribed nefazodone. 1999. Berthou F. et al: Inhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition.000 IU/L and a serum creatinine level of 2. He was diagnosed with rhabdomyolysis-induced acute renal failure (S. AIDS 11:268–269. June 2002). muscle weakness. the patient experienced worsening myalgias. Greenblatt DJ. The internist had heard that nefazodone (Serzone) was helpful for anxious depression and especially helpful for insomnia. he became increasingly anxious and depressed. Schmider J. 1998). He reported these symptoms to his internist. personal communication. and nefazodone is a strong competitive inhibitor of 3A4 (von Moltke et al. Neuvonen et al. In the week after reaching this dosage. 1997 von Moltke LL. 1998 Ketter TA. and poor concentration to his internist. reporting worsening terminal insomnia. Spence JD. In the emergency room. who advised the patient to go to an emergency room immediately.7 mg/dL. 1995 Merry C. Carlhant D. After some discussion with the patient. which led to an increase in the blood level of simvastatin. Drug Metab Dispos 26:257–260. Post RM. Mulcahy F. 2000 Iribarne C. 1996). Simvastatin is a 3A4 substrate (Gruer et al. Discussion This is an example of an inhibitor added to a substrate. et al: Saquinavir interaction with midazolam: pharmacokinetic considerations when prescribing protease inhibitors for patients with HIV disease. J Clin Pharmacol 36:783–791.122 Drug–Drug Interaction Primer References Dresser GK. et al: The emerging role of cytochrome P450 3A in psychopharmacology. After his father passed away. and by azole antifungal agents.

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

He asked his internist for a sleep aid. with the result that the zolpidem blood level at a dosage of 10 mg was far too low to promote sleep. 1998 Sutton D. but this did not help him get to sleep. which did reliably help him to fall asleep.124 Drug–Drug Interaction Primer buspirone area under the curve with the addition of diltiazem (Lamberg et al. Nadin L. The next night. leading to persistent onset insomnia. Once the diltiazem was discontinued. After he reported these events to his internist. and rifampin is a strong 3A4 inducer (Strayhorn et al. Zolpidem is principally a substrate of 3A4 (von Moltke et al. there was much more 3A4 available to metabolize the zolpidem than was expected. and he still did not feel at all drowsy. He would often dwell on these as he tried to get to sleep. The zolpidem was initially prescribed at a dosage that would generally help facilitate sleep. because rifampin was already present. he continued to increase the dosage. Clin Pharmacol Ther 63:640–645. et al: Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole. and the patient’s side effects remitted. However. 1997 Lamberg TS. 300 mg po qhs as needed. he tried the 5-mg dose of zolpidem. Kantola T. 1997). Discussion This is an example of a substrate added to an inducer. 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. Without consulting his internist. Kivisto KT. 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 . He found that only after he took a dose of at least 25 mg was he able to fall asleep promptly. for the insomnia. Neuvonen PJ: Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics of buspirone. 3A4 resumed its baseline (higher) level of metabolic activity. he was instead prescribed gabapentin (Neurontin). Lamberg TS. References Kivisto KT. and he was prescribed zolpidem (Ambien). 1998). 5–10 mg qhs prn for insomnia. 1999). The following night he tried 10 mg of zolpidem. Clin Pharmacol Ther 62:348–354. et al: Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. Butler AM. J Pharmacol Exp Ther 282:294–300. the buspirone blood level declined back to baseline.

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

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

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

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

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

Spence JD. the patient was experiencing significant daytime sedation. 0. 1994). Graci DM. who advised her to hold her triazolam that night. then another week of treatment. In this case. 1995) to over 24 hours (Varhe et al. In the course of that drive.5–5 hours (Hyman et al. Love. It has been demonstrated that itraconazole can lengthen the half-life of triazolam from 1. including midazolam (Versed) and alprazolam (Xanax) (Dresser et al. References Dresser GK. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition.25–0. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. personal communication. Ann Pharmacother 34:495–513. 2000 . She needed to make a 2-hour drive the following day.375 mg of her triazolam that very night. Clin Pharmacokinet 38:41–57. with slurring of her speech and ataxia. for which he prescribed itraconazole (Sporanox). 2001 Pai MP. as are all the other triazolobenzodiazepines. 200 mg bid for the first week. Despite these events. to be followed by a 3-week hiatus. August 2002). Itraconazole is a potent competitive inhibitor of 3A4 (von Moltke et al. Amsden GW: Macrolide drug interactions: an update. 2000 AVOIDABLE TRAGEDY A 47-year-old woman with recent sleep difficulties had been taking triazolam (Halcion). crossing four lanes of traffic and the median barrier before crashing into a car heading the opposite direction. prescribed by her family physician. She contacted her neurologist. Discussion This is an (especially tragic) example of an inhibitor added to a substrate. this effect accounted for the patient’s severe daytime sedation and the subsequent tragedy.5 mg qhs. By day 5 of the first week of itraconazole use. which led to a significant increase in the blood level and half-life of triazolam. 1996). and she was indeed more alert the next day. even though the dosage of triazolam had not been changed. She also developed a pedal onychomycosis. J Clin Pharmacol 41:823–832. the patient nonetheless opted to take 0. 2000). The addition of the itraconazole significantly impaired the ability of 3A4 to efficiently metabolize the triazolam. the patient fell deeply asleep at the wheel. Triazolam is a 3A4 substrate. killing herself and both persons in the other vehicle (R.130 Drug–Drug Interaction Primer Olesen OV.

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

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

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

et al: Addisonian crisis in a liver transplant patient due to fluconazole withdrawal. and an endocrinologist was consulted to address his sudden-onset adrenal insufficiency (Tiao et al. requiring emergent administration of additional intravenous cortisol to avert a potential disaster. 1999 NATURAL DISASTER (III) A 58-year-old man had just undergone a successful renal transplantation procedure. References Michalets EL. Within the next 5 days. with the result that the blood level of prednisone then precipitously declined. Clin Pharmacokinet 39:49–75. The presence of the fluconazole significantly impaired the ability of 3A4 to metabolize the prednisone. 1999). Backman JT. and fluconazole is a strong 2C9 inhibitor and a moderate 3A4 inhibitor (Michalets and Williams 2000. 2001). 2001 Tiao GM. Williams CR: Drug interactions with cisapride: clinical implications. and hypotension. His fluconazole was eventually discontinued. Klotz U: Pharmacokinetic considerations in the treatment of inflammatory bowel disease. Clin Pharmacol Ther 69:194–200. He also was prescribed standing fluconazole (Diflucan) as a prophylactic antifungal agent. Clin Transplant 13:62–64. Clin Pharmacokinet 40:723–751. He was being maintained on tacrolimus (Prograf). Weber FL. abdominal pain. Neuvonen M.134 Drug–Drug Interaction Primer INSUFFICIENCY A 42-year-old man had successfully undergone liver transplantation. titrated to a level . following which he was placed on standing prednisone (Deltasone) as an immunosuppressant. When the fluconazole was discontinued. 3A4 returned to its baseline (higher) level of functioning. He was quickly given supplementary intravenous cortisol. 2000 Niemi M. delirium. This caused the patient to experience an acute addisonian crisis. Discussion This is an example of reversal of inhibition. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. he experienced acute onset of fever. 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. 2001 Schwab M. This led to more efficient metabolism of prednisone by 3A4. Prednisone is a 3A4 substrate (Schwab and Klotz 2001). Niemi et al. vomiting. but he remained on prednisone. Martin J.

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

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

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

Eur J Clin Pharmacol 11:287–293. et al: Rifampin and rifabutin drug interactions: an update. Svendsen TL. et al: The influence of rifampin treatment on caffeine clearance in healthy man. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Chrisman CR. Arch Intern Med 162:985–992. 2001 Strayhorn VA. References Breyer-Pfaff U. J Clin Psychopharmacol 18:83–85. Anthony LB. 1998 Kay L. Drug Metab Dispos 29:1343–1348. Marschall HU. 1977 . Engel G. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. This interaction likely synergized with the extensive P450 interactions mentioned earlier. Johansson I. 2002 Heimark LD. et al: The mechanism of the warfarin–rifampin drug interaction. and rifampin is a UGT1A4 inducer (Ebert et al. Self TH: Update on rifampin drug interactions. Oertel R. Wachsmuth H: Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine. Richter E: Stimulation of drug metabolism by rifampicin in patients with cirrhosis or cholestasis measured by increased hexobarbital and tolbutamide clearance. et al: Induction of polymorphic 4′-hydroxylation of S-mephenytoin by rifampicin. Thong NQ. et al: Effects of rifampin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. 1995 Zhou HH. Clin Pharmacol Ther 42:388–394. 1987 Joos AA. Trager WF. Br J Clin Pharmacol 20:323–326. 1990 Zilly W. Breimer DD. 2001 Ebert U. Clozapine is a uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A4 substrate (Breyer-Pfaff and Wachsmuth 2001). Baciewicz AM. Kaschka WP: Pharmacokinetic interaction of clozapine and rifampin in a forensic patient with an atypical mycobacterial infection. J Hepatol 22:78–81.to sixfold decreases in clozapine blood levels (Finch et al. Wood AJ. et al: Influence of rifampicin and isoniazid on the kinetics of phenytoin. 2C9. 3A4. Eur J Clin Pharmacol 56:299–304. 2000 Eiermann B. even though the clozapine dosage had not been changed (Joos et al. Zysset T. 1998). Br J Clin Pharmacol 30:471–475.138 Drug–Drug Interaction Primer amount of 1A2. resulting in a sharp decline in the clozapine blood level. There was also a likely contribution from phase II glucuronidative metabolism. 1997 Finch CF. 2000). III. Kampmann JP. Studies have demonstrated that the addition of rifampin to clozapine can produce three. 2002). 1997 Wietholtz H. 1985 Olesen OV. J Clin Pharmacol 41:823–832. Baciewicz AM. Arch Intern Med 157:2453–2458. Br J Clin Pharmacol 44:439–446. and 2C19 that was available to metabolize the clozapine. Gibaldi M. Frank UG.

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

Oertel R. Gibaldi M. Baciewicz AM. et al: Rifampin and rifabutin drug interactions: an update. 2000 Eiermann B. she developed increasing sedation. Breimer DD. Eur J Clin Pharmacol 11:287–293. Marschall HU. et al: The mechanism of the warfarin– rifampin drug interaction. 2001 Strayhorn VA. Thong NQ. Kampmann JP. Self TH: Update on rifampin drug interactions. 2001 Ebert U. 1995 Zhou HH. Drug Metab Dispos 29:1343–1348. Trager WF. 455 ng/mL). 2002 Heimark LD. Svendsen TL. et al: Effects of rifampin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. 1987 Kay L. Br J Clin Pharmacol 44:439–446. Br J Clin Pharmacol 20:323–326. Engel G. however.140 Drug–Drug Interaction Primer back to the pre-rifampin baseline dosage (500 mg/day) in the weeks following discontinuation of the rifampin. Within the next 3 weeks. Wachsmuth H: Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine. J Hepatol 22:78–81. This would hopefully have avoided any acute increases in the clozapine blood level and accompanying complications. 1997 Wietholtz H. Zysset T. With the support and encouragement of her family and friends. 1997 Finch CF. she used a nicotine patch (prescribed by her internist) and abruptly stopped smoking. Baciewicz AM. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. et al: Induction of polymorphic 4′-hydroxylation of S-mephenytoin by rifampicin. III. 1990 Zilly W. Arch Intern Med 157:2453–2458. especially in view of her moderate hypertension (even while on clozapine) and family history of early demise from cardiac events. Arch Intern Med 162:985–992. Wood AJ. Johansson I. et al: The influence of rifampin treatment on caffeine clearance in healthy man. blurry vision. 1985 Olesen OV. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. 700 mg/day (blood level. During a routine checkup with her internist. and con- . J Clin Pharmacol 41:823–832. References Breyer-Pfaff U. he explained to her the importance of smoking cessation. Richter E: Stimulation of drug metabolism by rifampicin in patients with cirrhosis or cholestasis measured by increased hexobarbital and tolbutamide clearance. Chrisman CR. 1977 SMOKING GUN (II) A 47-year-old woman with chronic paranoid schizophrenia was being well maintained on clozapine (Clozaril). Anthony LB. Br J Clin Pharmacol 30:471–475. dizziness when rising from a sitting position. et al: Influence of rifampicin and isoniazid on the kinetics of phenytoin. Eur J Clin Pharmacol 56:299–304. Clin Pharmacol Ther 42:388–394.

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

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

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

which led to the emergence of olanzapine side effects (sedation and constipation) (Pies 2002). 2000 GI JOE A 27-year-old man with chronic paranoid schizophrenia was being stably maintained on olanzapine (Zyprexa). Eur J Clin Pharmacol 56:585– 589. Engel G. Drug Metab Dispos 24:1134–1138. When his psychiatrist was consulted. Neuvonen PJ: Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia. the blood level of olanzapine rose. the patient experienced increased sedation and constipation. even though there had been no increase in the olanzapine dosage. Monshouwer M. and his doctor prescribed cimetidine (Tagamet). 1997 McLellan RA. although the majority of this inhibition likely occurred at 1A2. References Callaghan JT. 2001 Raaska K. Drobitch RK. et al: Fluoroquinolone antibiotics inhibit cytochrome P450–mediated microsomal drug metabolism in rat and human. which promptly led to a remission of these symptoms. which led to a remission of these side effects with a preservation of antipsychotic efficacy. although it is also metabolized by 2D6 and phase II glucuronidation (Callaghan et al. Olanzapine is a 1A2 substrate. 1999). Br J Clin Pharmacol 44:439–446. 1996 Olesen OV. Clin Pharmacokinet 37:177–193. Discussion This is an example of an inhibitor added to a substrate. Johansson I. 300 mg qid. 2D6. Bergstrom RF. he decreased the dosage of olanzapine to 15 mg/day. He developed some persistent heartburn. The patient remained psychiatrically stable throughout and into the future. Ptak LR. et al: The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. and 3A4 (Martinez et al. which led him to visit his primary care physician. J Clin Pharmacol 41:823–832. for cost reasons. et al: Olanzapine: pharmacokinetic and pharmacodynamic profile. After a gastrointestinal workup. Cimetidine is a “paninhibitor” that strongly inhibits 1A2.144 Drug–Drug Interaction Primer Eiermann B. 1A2 and 2D6 were impaired in their ability to contribute to olanzapine’s metabolism. 1999). After 5 days. Linnet K: Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. 1999 . 25 mg/day. Thus. With the addition of the cimetidine. he was diagnosed with gastroesophageal reflux disease. The psychiatrist compensated for the decreased metabolism of olanzapine by decreasing the dosage from 25 mg/day to 15 mg/day.

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

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

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

1998). and omeprazole is a strong inhibitor of 2C19. Within several days.148 Drug–Drug Interaction Primer References Blum RA. as well as an inducer of 1A2 (Furuta et al. He coped with this loss by increasing his food intake. especially in the late evenings. et al: Effect of fluconazole on the disposition of phenytoin. he was frankly unsteady on his feet and felt drunk. 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). so that the inhibition . Clin Pharmacol Ther 69:194–200. 40 mg/day. The enzyme 2C9 was not able to fully compensate for this 2C19 inhibition. Epilepsia 39:1317–1323. the addition of omeprazole significantly impaired the ability of 2C19 to contribute to the efficient metabolism of phenytoin. and he was quite demoralized in the wake of the breakup. 2001. Ieiri I. He had recently broken up with a woman he had been dating for 18 months. Ann Pharmacother 28:191–195.1 µg/mL. who prescribed omeprazole (Prilosec). He eventually made an appointment with his internist. Wilton JH. Clin Pharmacol Ther 49:420–425. he also experienced a worsening of heartburn pain. Hilligoss DM. phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. 1994). Mamiya et al. 1998 Niemi M. Backman JT. In addition to gaining several pounds. 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.9 µg/mL. 1994. Shimamoto J. Zenon GJ 3rd. His most recent phenytoin blood level was 16. Nousbaum et al. First. He contacted his neurologist and informed him of his current symptoms as well as of the fact that he was now taking omeprazole. which he had felt off and on for the past 5 years. where his phenytoin blood level was found to be 27. After 1 week on the omeprazole. the patient began to experience increased sedation and a sensation of being less mentally acute. 2001 FROM HEARTBREAK TO HEARTBURN A 58-year-old widower had been chronically taking phenytoin (Dilantin). 1994 Mamiya K. for a seizure disorder. 1991 Cadle RM. The neurologist told him to call 911 for an ambulance to transport him to the nearest emergency room. Neuvonen M. Rodriguez-Barradas MC. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. et al: Fluconazole-induced symptomatic phenytoin toxicity. Thus. 300 mg bid.

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

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

She was initially treated with intravenous heparin and then transitioned to warfarin (Coumadin). Discussion This is an example of an inhibitor added to a substrate. Warfarin’s metabolism is very complex. Third. an increase in R-warfarin levels led to more inhibition of the metabolism of S-warfarin. R-warfarin does produce some direct anticoagulant effect. and he ordered a stat prothrombin time.0 for another 10 days. The more active S-warfarin isomer is metabolized primarily by P450 2C9 (Heimark et al.8. The addition of fluvoxamine led to an increase in the INR through several mechanisms. First. She was surprised that she immediately developed a large and ugly bruise on her arm as a result. Fluvoxamine is a strong inhibitor of 1A2. the patient accidentally. 1995). yielding higher S-warfarin levels.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. The fluvoxamine was immediately discontinued. 1991). she experienced a recurrence of her major depressive disorder. and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. fluvoxamine’s inhibition of 1A2 and 3A4 yielded an increase in R-warfarin. 2002. bumped her arm on the side rail of her hospital bed. but her INR did not fall below 3. 5 mg/day (international normalized ratio [INR]. fluvoxamine significantly impaired the ability of 2C9 to metabolize the S-warfarin. which placed the patient in a pathologically hypocoagulable state in which she bruised very easily and was in danger of vascular hemorrhage. 2C9. Although it is a less potent anticoagulant than S-warfarin. even though the dosage of warfarin had remained constant throughout (Yap and Low 1999). von Moltke et al. Linder and Valdes 1999). but lightly. titrating the medication upward to a dosage of 100 mg/day. Her internist prescribed fluvoxamine (Luvox). Niemi et al. After 1 week of taking this dosage of fluvoxamine.4). After 3 weeks in the hospital. leading to an increase in the blood level of this warfarin isomer. These combined influences caused a significant increase in the patient’s INR. She informed her internist about this. Second. The internist eventually had to administer vitamin K to address her persistently high INR. The less active R-warfarin isomer is metabolized primarily at 1A2 (Lehmann 2000). Thus. 2. 2001. . R-warfarin is itself an inhibitor of P450 2C9 (Kunze et al. to almost 2½ times the baseline value. which revealed an INR of 5. 1987.

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

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

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

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

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

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

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

a process along these lines is reasonably inferable. 1998 .Internal Medicine Case Vignettes 159 with 1A2 serving as a secondary enzyme (Venkatakrishnan et al. 1993 Venkatakrishnan K. Mol Diagn 4:365–379. which led to an increase in the blood level of amitriptyline + nortriptyline. Lennard MS. Wrighton SA: Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. as evidenced by the increase in the anticholinergic effects of amitriptyline. This explains both the quantity and the color of the urine drained by catheterization of her bladder. Belpaire FM: Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug–drug interactions: an update. Greenblatt DJ. 1987 Hemeryck A. 2000 Stevens JC. 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. von Moltke LL. J Clin Pharmacol 38:112–121. et al: Metabolic enantiomeric interactions: the inhibition of human (S)-warfarin-7-hydroxylase by (R)-warfarin. Even though this was unconfirmed by an actual blood level. Trager WF. 2002 Hesse LM. Tucker GT. et al: The mechanism of the warfarin–rifampin drug interaction. Pharmacotherapy 20:1464–1468. Chiba K. Gibaldi M. et al: Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4. Yamamoto T. 1999 Sayal KS. Duncan-McConnell DA. Acta Psychiatr Scand 102:250–255. Taylor DM: Psychotropic interactions with warfarin. et al: CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. References Crewe HK. Eddy AC. Curr Drug Metab 3:13–37. Clin Pharmacol Ther 42:388–394. J Pharmacol Exp Ther 266:964–971. Venkatakrishnan K. Br J Clin Pharmacol 40:481–485. et al: The effect of selective serotonin reuptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Drug Metab Dispos 28:1176–1183. 1992 Heimark LD. leading to inability to void. McConnell HW. 1991 Lehmann DE: Enzymatic shunting: resolving the acetaminophen-warfarin controversy. 3A4. Br J Clin Pharmacol 34:262–265. 2000 Linder MW. Valdes R Jr: Pharmacogenetics in the practice of laboratory medicine. The fluoxetine significantly impaired the ability of 2D6. Gibaldi M. 1995 Kunze KL. et al: The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4′-hydroxylase activity in human liver microsomes. Court MH. and 2C19 to contribute to the metabolism of amitriptyline. 2000 Kobayashi K. 1998). Chirality 3:24–29.

SSRI antidepressants. She was prescribed fluconazole (Diflucan). Carbamazepine is primarily a 3A4 substrate. the 3A4 and 2C9 inhibition resulted in an increased blood level of carbamazepine. 2002. Her medical comorbidities included type II diabetes mellitus. et al: Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. In the emergency room. 2C9. 2002). However. Harmatz JS. and incoordination. and phase II metabolism (uridine 5′-diphosphate glucuronosyltransferase [UGT] 2B7) making minor contributions to carbamazepine’s metabolism (Pearce et al. 2004). her carbamazepine level was 19. Because the activity of 1A2 was not sufficient to compensate for this effect. with 1A2. nefazodone and venlafaxine. 1994) and a moderate 3A4 inhibitor (Eap et al. The vancomycin successfully eradicated the infection. confusion. J Pharmacol Exp Ther 276:370–379. and a long-standing seizure disorder that had been well controlled with carbamazepine. Spina et al. her wound was not healing well. Discussion This is an example of an inhibitor added to a substrate. With the addition of fluconazole. Three days later.4 µg/mL. even though the carbamazepine dosage had remained constant (Nair and Morris 1999). 3A4 and 2C9 were impaired in their ability to efficiently contribute to the metabolism of the carbamazepine. she was stuporous and required readmission to the hospital. 2C8. controlled by diet alone. 2B6. She was treated with 8 weeks of intravenous vancomycin. Fluconazole is a strong 2C9 inhibitor (Cadle et al.160 Drug–Drug Interaction Primer von Moltke LL. In the weeks after surgery. 1996a von Moltke LL. 1996. after 1 week she experienced increasing drowsiness. 2E1. and she began to experience intermittent fevers. 900 mg/day (blood level. but the patient then developed a diffuse candidal rash. Greenblatt DJ. A wound culture revealed infection with methicillin-resistant Staphylococcus aureus.2 µg/mL). . Greenblatt DJ. Staines et al. during which she was transitioned to home care with intravenous antibiotic treatment. Psychopharmacology (Berl) 128:398–407. 9. Duan SX. 200 mg on day 1 and 100 mg/day thereafter for at least 2 weeks. et al: Phenacetin O-deethylation by human liver microsomes in vitro: inhibition by chemical probes. 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

Drug–Drug Interaction Primer

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.

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

1982.170 Drug–Drug Interaction Primer Discussion This is an example of plasma protein binding displacement accompanied by metabolic inhibition. Abbott Laboratories. Divalproex is tightly bound to plasma proteins and thus may displace and be displaced by other tightly bound compounds. This occurs because it is the metabolism of the free fraction that is being inhibited. 2006). 1986). However. and this process is responsible for roughly 40% of valproate’s metabolism. 2006) suggest that the necessary dosage of aspirin to increase free valproate levels might be considerably lower than that. This case and others like it (Sandson et al. aspirin is an inhibitor of β-oxidation. Neurology 37:1392–1394. North Chicago. Additionally. there has never been a rigorous attempt to establish the lowest dosage of aspirin that can produce this effect. such as phenytoin and nonsteroidal anti-inflammatory drugs (Abbott Laboratories 2002. J Pediatr 101:142– 144. Aspirin is also highly plasma protein– bound (Lim et al. Kassam J.900 mg/day) can produce up to fourfold increases in free valproate (Orr et al. et al: The effect of acetylsalicylic acid on serum free valproate concentrations and valproate clearance in children. 1986 Abbott Laboratories: Depakote (package insert). Dooley JM. 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. Grimaldi et al. 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. IL. Camfield PR. Farrell et al. the marked increase in the free/active concentration led to the development of marked sedation and incoordination. 1982 Goulden KJ. Kodama et al. Orr JM. 1982). Because this interaction can produce greater increases in free concentrations than in total concentrations of valproate. Orr JM. These two factors combine to produce modest increases in total valproate levels. The existing literature reports that combinations of valproate with “antipyretic” doses of aspirin (approximately 3. Goulden et al. References Abbott FS. Abbott FS. et al: The effect of aspirin on valproic acid metabolism. et al: Clinical valproate toxicity induced by acetylsalicylic acid. Clin Pharmacol Ther 40:94–100. In this case. but disproportionate and often clinically significant increases in free valproate concentrations (Abbott et al. 1984. 1987). 1986. 2002 Farrell K. 2001). 1987 .

et al: Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects. Crema F. J Pharm Pharmacol 38:795– 800. as an anticoagulant after her mitral valve replacement procedure.’ J Intern Med 241:337–339.8 and her partial thromboplastin time was greater than 120 seconds (Yu et al. but fortunately not to a fatal extent in this case. Abbott FS. 1982 Sandson N. 2001 Lim CF. Am J Psychiatry 163:1891–1896. These anticoagulant effects synergized to produce spontaneous hemorrhagic events.Internal Medicine Case Vignettes 171 Grimaldi R. who recommended danshen (Salvia miltiorrhiza) for this problem. Kuranari M. She quickly reported to a local emergency room. 1986 Orr JM. 1997). Chan JC. 2006 HERBAL HEMORRHAGE A 35-year-old woman with rheumatic heart disease had been taking warfarin (Coumadin).S. Within the next week. Lecchini S. et al: Non-isotopic spectrophotometric determination of the unbound fraction of drugs in serum. Eur J Drug Metab Pharmacokinet 9:359– 363. Barned JM. 3. et al: Gender. Bourke DL. 2000 Yu CM. the woman was alarmed to discover she was experiencing spontaneous subcutaneous hematoma formation.2). Sanderson JE: Chinese herbs and warfarin potentiation by ‘danshen. 2000). Hamilton W. where her INR was 9. et al: An interaction between aspirin and valproate: the relevance of plasma protein displacement drug–drug interactions. Clin Pharmacol Ther 31:642–649. 1984 Kodama Y. Rabinovich A: A review of herb–drug interactions: documented and theoretical. et al: In vivo plasma protein binding interaction between valproic acid and naproxen. U. Discussion This is an example of pharmacodynamic synergy resulting in excessive anticoagulation. She was experiencing menstrual irregularity. Wynne KN. 5 mg/day (international normalized ratio [INR].or age-related binding characteristics of valproic acid to serum proteins in adult patients with epilepsy. Marcucci C. Warfarin functions as an effective anticoagulant by virtue of its ability to inhibit specific steps of the coagulation cascade. Pharmacist Home 25:8. 1997 . References Lambrecht JE. as measured by the INR. Danshen is able to inhibit platelet aggregation (Lambrecht et al. Eur J Pharm Biopharm 52:57–63. so she visited an herbalist. Kodama H. Farrell K.

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

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

Although it is not known exactly what antihypertensive medications Mr. 400 mg/day (blood level. III. 1997. misadventure. Trager WF. Kampmann JP. In either case. Kay et al.174 Drug–Drug Interaction Primer Discussion This is an example of an inducer added to a substrate. 1987. Zhou et al. McQueen RH. et al: Effects of rifampin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. Clin Pharmacol Ther 42:388–394. 1995 Ebert U. Svendsen TL. 17. Anthony LB. 1990. 1998 Zhou HH. et al: The influence of rifampin treatment on caffeine clearance in healthy man. Self TH: Update on rifampin drug interactions. 1985 Strayhorn VA. 1998). Wietholtz et al. 2000 Heimark LD. Rifampin is a pan-inducer of assorted P450 and phase II enzymes (Ebert et al.6 µg/mL). Richter E: Stimulation of drug metabolism by rifampicin in patients with cirrhosis or cholestasis measured by increased hexobarbital and tolbutamide clearance. Eur J Clin Pharmacol 11:287–293. Patterson JH. Baciewicz AM. 1995 Williamson KM. whether by accident. Breimer DD. 1990 Zilly W. Zilly et al. Amar J: Drug interactions with antihypertensive drugs. Wood AJ. 1997 Wietholtz H. et al: Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers. 2000. . Arch Intern Med 157:2453–2458. et al: The mechanism of the warfarin– rifampin drug interaction. it is reasonable to assume that their metabolism was induced by the rifampin. Eur J Clin Pharmacol 56:299–304. Br J Clin Pharmacol 20:323–326. 1985. et al: Induction of polymorphic 4′ hydroxylation of S-mephenytoin by rifampicin. Therapie 50:221–226. calcium channel blockers. Gibaldi M. J Hepatol 22:78–81. Oertel R. 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. 1977 TREATMENT FAILURE A 72-year-old female with a lifelong seizure disorder had been well maintained on phenytoin (Dilantin). Strayhorn et al. Thong NQ. angiotensin-converting enzyme inhibitors. Marschall HU. et al: Influence of rifampicin and isoniazid on the kinetics of phenytoin. This is known to be the case for various β-blockers. 1987 Kay L. Zysset T. this episode briefly made the world aware of the potential for drug interactions to have deadly consequences. Heimark et al. Milosevic was taking. or design. and angiotensin receptor blockers (Chamontin and Amar 1995. References Chamontin B. Williamson et al. 1995. 1977). Br J Clin Pharmacol 30:471–475. Clin Pharmacol Ther 63:316–323.

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

Additions of substrates to inhibitors (or inducers) often do not produce acute complications. 2 weeks after the TMP/SMX had been discontinued. 2005 . 4 mg/day (international normalized ratio [INR]. 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. References Glasheen JJ. Fugit RV. 1987. Warfarin’s metabolism is very complex. 2002). Prochazka AV: The risk of overcoagulation with antibiotic use in outpatients on stable warfarin regimens. This case also illustrates the importance of recognizing drug interactions even when they do not produce acute difficulties. where a computed tomography scan of the brain confirmed an acute ischemic stroke. Discussion This is an example of a substrate added to an inhibitor.5. provided that one is dosing substrate in accordance with blood levels. Linder and Valdes 1999). when warfarin was added to TMP/SMX. which predisposed her to a cerebrovascular accident in the context of undertreated atrial fibrillation. However. Sulfamethoxazole is a known inhibitor of P450 2C9 (Wen et al. 2005. 2C9 was able to resume its higher baseline level of activity. and/or side effects rather than per preset dosing guidelines. the patient’s CD4 count rose to a value of 257/mm3. 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). she then developed atrial fibrillation and was additionally treated with warfarin (Coumadin).176 Drug–Drug Interaction Primer SMX. J Gen Intern Med 20:653–656. the patient experienced acute onset of slurred speech and right sided hemiparesis. With appropriate highly active antiretroviral therapy. With the discontinuation of the TMP/SMX. At this time. The more active S-warfarin isomer is metabolized primarily by P450 2C9 (Heimark et al. followed by reversal of inhibition. However. The patient was taken to the nearest emergency room. Her INR in the emergency room had declined to 1. Kaufman and Fauver 1980). This produced a decrease in warfarin levels and a corresponding drop in the patient’s INR. if the drug interaction is not recognized.4). clinical response. 2C9 was impaired in its ability to contribute to the metabolism of warfarin. the patient’s internist opted to discontinue the TMP/SMX in accordance with recent research regarding appropriate PCP prophylaxis. Thus. 2.

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

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

via cigarette smoking. restlessness. sister.Internal Medicine Case Vignettes 179 References Johnson JF. When he notified his pediatrician about his difficulties. With the cessation of smoking.5 µg/mL). DICP 24:250–251. 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. Moreover. Clin Pharmacokinet 44:1209–1225. Mamdani M. she asked the patient to report to the laboratory in the morning for a theophylline level. After much encouragement from his parents. and pediatrician. Kopp A. these other symptoms seemed to worsen over the next several days. Backman JT. the pediatrician instructed the patient to take no theophylline for 24 hours and then to decrease his dosage to 600 mg/day thereafter. When it was discovered that his theophylline level had risen to 26. Gallagher S. 2001 Kirchheiner J. Goldammer M. Drug Metab Dispos 30:631–635. Discussion This is an example of reversal of induction. et al: Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9. He had been receiving theophylline (Theodur). respectively. 1998. et al: Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. but he also experienced palpitations. and polyuria. theophylline dosages typically need . 900 mg/day (blood level.” 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. although his cravings eventually diminished somewhat. Theophylline is a substrate of P450 1A2 (Zhang and Kaminsky 1995). occasional vomiting. Wang JS. is a significant 1A2 inducer (Schrenk et al. 2003 Kidd RS. Zevin and Benowitz 1999). JAMA 289:1652–1658. 2005 Wen X. Tobacco use. et al: Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. 1990 Juurlink DN. et al: Drug–drug interactions among elderly patients hospitalized for drug toxicity.4 µg/mL. 2002 NIC FIT A 17-year-old male adolescent with asthma had nonetheless been smoking one pack of cigarettes each day. the patient’s available complement of 1A2 steadily decreased over the next several days. 16. In this situation. Pharmacogenetics 11:803– 808. Roots I. Curry TB. he decided to quit smoking “cold turkey. Dobmeier ME: Symptomatic hypoglycemia secondary to a glipizidetrimethoprim/sulfamethoxazole drug interaction.

Eur J Clin Pharmacol 53:361–367. 1995 INOTROPIC ANOREXIA A 91-year-old female with known congestive heart failure (ejection fraction. et al: A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. 1998 Zevin S. the digoxin level had risen to 2. Within four days.2 ng/mL. there was greater bioavailability and absorption of digoxin from the gut.125 mg/day. Biochem Pharmacol 50:205–211. and her levels remained in her normal range. 10 mg/day. 0. Digoxin is a substrate of the P-glycoprotein transport protein (PauliMagnus et al. The internist discontinued both the fluoxetine and the digoxin. and theophylline disposition. After the death of her grandson at the hands of a drunk driver. 1987 Schrenk D. 1987). Fluoxetine has been demonstrated to be an inhibitor of the P-glycoprotein transporter (Weiss et al.8 ng/mL.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. she became acutely depressed. the addition of fluoxetine significantly impaired the ability of the P-glycoprotein transporter to extrude digoxin from enterocytes back into the gut lumen. 10 mg/day. A digoxin level obtained at that time was 4. Jacob P 3rd: Cigarette abstinence. nicotine gum. digoxin alone was eventually restarted. and her anorexia and confusion were returning. and a different antidepressant was chosen for a subsequent trial (Leibovitz et al. One week later. Ann Intern Med 106:553–555. leading to an increase in the . References Lee BL. On this dosage. Morike K. Her internist prescribed fluoxetine (Prozac). Because more digoxin was retained in enterocytes. Five days later. 20%) was stably maintained on digoxin (Lanoxin). Kaminsky LS: Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. 2003).4 ng/mL. because her depression persisted. Discussion This is an example of an inhibitor added to a substrate. her digoxin levels ranged from 1. Benowitz NL.0 to 1. However. about 1 month later the internist again prescribed fluoxetine.125 mg/day. Thus. Benowitz NL: Drug interactions with tobacco smoking: an update. 0. The patient was restarted on digoxin. 1999 Zhang ZY. the patient developed significant anorexia and mild confusion. Clin Pharmacokinet 36:425–438. 2001). the anorexia and confusion had remitted and the digoxin level had returned to normal. Brockmeier D. Fluoxetine and digoxin were again discontinued. 1998).

20 mg/day (Spier and Frontera 1991). lethargy. Within 5 days. alpha-methyldigoxin and beta-acetyldigoxin. 1. fluvoxamine. Digoxin is a substrate of the P-glycoprotein transport pump (PauliMagnus et al.5 ng/mL).125 mg/day (blood level. 2003 COMMUNITY-ACQUIRED TOXICITY A 72-year-old male with congestive heart failure was taking digoxin (Lanoxin). et al: P-glycoprotein–mediated transport of digitoxin. References Leibovitz A. Ann Intern Med 158:1152–1153.9. 0. One winter. 2001). When he reported these symptoms to his internist. 250 mg bid for 10 days. Dormann SM. She died abruptly and unexpectedly several days after starting fluoxetine. Clarithromycin has been demonstrated to be an inhib- . At her regular dosage. 2001 Spier SA. Although drug interactions resulting purely from alterations in the functioning of the P-glycoprotein transporter are relatively infrequent. 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. and paroxetine are all thought to moderately inhibit the P-glycoprotein transporter (Weiss et al. the patient experienced new-onset nausea. Fluoxetine. who diagnosed a community-acquired pneumonia and started the patient on clarithromycin (Biaxin). Godel A. he developed a progressive cough. Gil I. Bilchinsky T.Internal Medicine Case Vignettes 181 blood level of digoxin (Leibovitz et al.1 ng/mL. 1991 Weiss J. J Pharmacol Exp Ther 305:197–204. 2003). which had risen to 2. 1998 Pauli-Magnus C. then started a trial of moxifloxacin (Avelox). Naunyn Schmiedebergs Arch Pharmacol 363:337–343. Discussion This is an example of an inhibitor added to a substrate. Frontera MA: Unexpected deaths in depressed medical inpatients treated with fluoxetine. and a persistent low-grade fever. et al: Elevated serum digoxin level associated with coadministered fluoxetine. 1998). this factor is probably underestimated in both frequency and severity as a meaningful contributor to clinically significant drug interactions. the blurry-vision complaint led the physician to send the patient to the laboratory for a digoxin level. Murdter T. sertraline. vomiting. which was effective and which the patient tolerated without difficulty. J Clin Psychiatry 52:377–382. The internist discontinued the clarithromycin. Martin-Facklam M. held the patient’s digoxin for 2 days. and blurry vision. et al: Inhibition of P-glycoprotein by newer antidepressants. He visited his internist. she had a digoxin blood level of 2.

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

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

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

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

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

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

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

Oesterheld. Clin Pharmacokinet 31:198–214. Molloy M. Pisani F. 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. J Clin Psychiatry 49:448–449.190 Drug–Drug Interaction Primer were quite distinct from his Tourette’s-related motor tics. resulting in a rise in the blood level of risperidone and a subsequent remission of the dyskinesias. Bork J: Risperidone and cytochrome P450 3A. Eur J Clin Pharmacol 59:879– 882. Spina et al. personal communication. and he was started on divalproex sodium (Depakote). Discussion This is an example of an inducer added to a substrate. Suzuki A. 1996 Spina E. References Arana GW. 1996. Ono et al. J Clin Psychiatry 58:450. 2000 Ucar M. 2001 Ono S. 2000) and the subsequent emergence of withdrawal dyskinesias. specifically including 3A4 (Arana et al. 2002. Luurila H. Ucar et al. The dyskinesias persisted for roughly 10 days but then eventually remitted (J. May 2002). It is also likely that the methylphenidate contributed to the development of the dyskinesias on a pharmacodynamic level. 1997 DeVane CL. 2002 Spina E. 2004 . this resulted in an acute two. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. J Clin Psychopharmacol 21:408–416.to threefold decrease in the blood level of risperidone (deLeon and Bork 1997. Over the span of 2 weeks. Epstein S. Nemeroff CB: An evaluation of risperidone drug interactions. Neuvonen M. Just as the presence of carbamazepine led to a gradual increase in the amount of 3A4. Mihara K. Avenoso A. 1988. Ther Drug Monit 22:481–485. Facciola G. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Risperidone is a substrate of 2D6 and 3A4 (DeVane and Nemeroff 2001). 2004). et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. 1988 deLeon J. Spina et al. 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. and carbamazepine is an inducer of multiple P450 enzymes. Psychopharmacology (Berl) 162:50–54.R. et al: Plasma concentrations of risperidone and 9hydroxyrisperidone: effect of comedication with carbamazepine or valproate. The patient’s carbamazepine was then discontinued. et al: Significant pharmacokinetic interaction between risperidone and carbamazepine: its relationship with CYP2D6 genotypes.

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

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

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

Alprazolam is a 3A4 substrate (Dresser et al. Clin Pharmacokinet 31:198–214. with instructions to discontinue her alprazolam and to contact her internist immediately if any of these symptoms should recur. 1988. This resulted in a decrease in the blood level of alprazolam (Arana et al. Luurila H. 2000 Spina E. The astute emergency room physician addressed this difficulty by changing from alprazolam to lorazepam. and her blood pressure was 150/95 mm Hg. References Arana GW. During the recovery period. The addition of the carbamazepine led to an increase in the amount of 3A4 that was available to metabolize the alprazolam. Clin Pharmacokinet 38:41–57. She was given lorazepam (Ativan). he recovered fully from the sequelae of his fall. 2000).194 Drug–Drug Interaction Primer told her to report to the nearest emergency room. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. 2 mg po. Pisani F. Discussion This is an example of an inducer added to a substrate. 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). 1996 Ucar M. 1996. Neuvonen M. he experienced a seizure and was placed on phenytoin (Dilantin) at a therapeutic dosage. Spence JD. Her heart rate was found to be 116 beats per minute. specifically including 3A4 (Arana et al. Spina et al. Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. stat. 1988) to the extent that the patient actually entered into a state of mild benzodiazepine withdrawal. Epstein S. and a prescription for 1 mg qid. 2004). Eur J Clin Pharmacol 59:879– 882. He then fell from a ladder and suffered a closed head injury. Ucar et al. et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. 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. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. 1988 Dresser GK. although he remained on the phenytoin for . Over the next month. and carbamazepine is an inducer of multiple P450 enzymes. Molloy M. J Clin Psychiatry 49:448– 449.

he felt frankly “high” and reported this to his neurologist and his counselor at the methadone clinic. Raucy 2003). 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. and phenytoin is an inducer of multiple P450 enzymes. After consulting with his neurologist. Atorvastatin is a 3A4 substrate (Beaird 2000). 2002. He had been doing well. the patient experienced increasing sedation and incoordination. References Beaird SL: HMG-CoA reductase inhibitors: assessing differences in drug interactions and safety profiles. Dominiczak MH: Efficacy of statin therapy: possible effect of phenytoin. even though the dosage had not been changed (Khandwala 2006. 2002 Khandwala HM: Lipid lowering inefficiency of high-dose statin therapy due to concurrent use of phenytoin. 2006 Murphy MJ. Discussion This is an example of an inducer added to a substrate. In the weeks during which the phenytoin was tapered. 400 mg/day (blood level. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. This resulted in a decrease in the blood level of atorvastatin. Within 3 days of the discontinuation of the phenytoin. After some discussion. specifically including 3A4 (Gibson et al. the psychiatrist at the methadone clinic decreased . and methadone (Dolophine). 16. During his next routine visit with his internist. he was crossed over from the phenytoin to divalproex sodium (Depakote). The addition of phenytoin led to increased production of 3A4 and thus more efficient metabolism of the atorvastatin. 2000 Gibson GG. 80 mg/day. his cholesterol level had risen to 451 mg/dL. el-Sankary W. South Med J 99:1385–1387. from the methadone clinic at which he was enrolled. which led to a significant increase in the serum cholesterol level. Murphy and Dominiczak 1999). Toxicology 181–182:199–202. 1999 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Postgrad Med J 75:359–360. Drug Metab Dispos 31:533–539.3 µg/mL). 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.Neurology Case Vignettes 195 seizure prophylaxis. but he began to develop gum hyperplasia and enlargement of his lips. J Am Pharm Assoc 40:637–644.

Stahle L: Lamotrigine drug interactions in a TDM material. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. Baird S. 2002 Iribarne C. Pond SM. The clinic psychiatrist compensated for this reversal of induction by halving the methadone dosage. 300 mg/day (blood levels generally around 16 µg/mL). 1996 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Methadone is a substrate of 3A4 (Iribarne et al. for the past 5 years. 1998. she awoke with tingling on . 3A4. 2003 Tong TG. 1981 CLOTS A 45-year-old woman with a seizure disorder had been successfully treated with phenytoin (Dilantin). Chem Res Toxicol 9:365–373. even though the methadone dosage had not been increased. Kreek MJ. specifically including 2C9. One morning. 1998 Gibson GG. The original appropriate dosage of methadone was influenced by the presence of the phenytoin. et al: Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Ther Drug Monit 21:171–174.196 Drug–Drug Interaction Primer his methadone dosage to 40 mg/day. Thus. Ther Drug Monit 20:60–62. Seymour MA: Phenytoin auto-induction. References Bottiger Y. 1999 Chetty M. 2002. This necessitated a higher dosage of methadone than would have been needed if the phenytoin had not been present (Tong et al. which provided therapeutic efficacy and a remission of intoxication. 1999. This led to an increase in the blood level of methadone. Miller R. the amount of 3A4 decreased over the succeeding 2–3 weeks. 1981). Toxicology 181–182:199–202. Chetty et al. 2C19. with the taper and discontinuation of the phenytoin. which returned 3A4 to its lower baseline level of activity. Ann Intern Med 94:349–351. which provided relief from his cravings and a cessation of his intoxicated state. Drug Metab Dispos 31:533–539. el-Sankary W. 1996). and phenytoin is an inducer of multiple enzymes. Gibson et al. Berthou F. Svensson JO. Raucy 2003). Discussion This is an example of reversal of induction. and uridine 5′-diphosphate glucuronosyltransferase 1A4 (Bottiger et al. which increased the amount of 3A4 that was available to metabolize the methadone. et al: Phenytoin-induced methadone withdrawal.

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

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

et al: Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. 1996. 1988. His parents were awaiting a consultation with a pediatric urologist when the patient experienced a seizure. 2004. 7-ethoxycoumarin. and 1A2 (Yang et al. 2B6. Within 2 weeks. Faucette et al. 2001 Spina E. Spina et al. specifically including 1A2. 2D6. Tybring G. et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. 50 mg/day (no blood levels were obtained). responded to a trial of imipramine (Tofranil). Carbamazepine is an inducer of multiple P450 enzymes. 1999). and 3A4 (Arana et al. et al: Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects. Pollicino AM. Discussion This is an example of an inducer added to a substrate. Krausz KW. 1999 ENURESIS (II) A 10-year-old boy with persistent nocturnal enuresis. 2C9. 1993 von Moltke LL.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). 1995 Yang TJ. Imipramine is a tertiary-amine tricyclic antidepressant whose metabolism depends most on the intact functioning of 2C19. 2002 Niemi M. et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Drug Metab Dispos 27:102–109. Clin Pharmacol Ther 71:141–152. Sai Y. References Christensen M. 3A4. Clin Pharmacol Ther 69:194–200. Parker et al. to address his newonset seizure disorder. 1998. 6.8 µg/mL). Mihara K. Neuvonen M. and imipramine metabolism. Court MH. J Clin Psychopharmacol 15:125–131. He was eventually placed on carbamazepine (Tegretol). in addition to his imipramine. Miners and Birkett 1998. the patient was again consistently enuretic at night. Greenblatt DJ. Backman JT. 600 mg/day (blood level. Ther Drug Monit 15:243–246. . which had not responded to behavioral interventions. et al: Eight inhibitory monoclonal antibodies define the role of individual P450s in human liver microsomal diazepam. Avenoso A.

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

2001. and this led to a lower haloperidol blood level. Part of this decrease in the haloperidol blood level may also be attributable to the induction of phase II glucuronidation. 1998. 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. Haloperidol is metabolized by 3A4. within 2 months of starting the phenytoin. 1999. This decrease in the haloperidol blood level allowed for a reemergence of active delusions and the patient’s accompanying clinical decompensation. Armstrong. haloperidol also relies on phase II glucuronidation for a significant portion of its metabolism.C. 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. specifically including 2C9. 300 mg/day (blood level. producing a blood level of 7.2 ng/mL. which was effective in preventing further seizures.7 µg/mL). the amount of 3A4 that was available to metabolize the haloperidol increased. because that is considered the minimum effective blood level (although this threshold is far from reliable). the patient refused to leave his apartment except for grocery shopping and visiting his psychiatrist. To protect himself. 2002. May 2002). 2002). However. personal communication. 1A2. Phenytoin is an inducer of multiple enzymes. The patient found this state of affairs quite upsetting and agreed to be hospitalized. he began to experience a decrease in the intensity of his paranoid and grandiose delusions (S. Once his haloperidol dosage was increased to 40 mg/day. Although there was no baseline haloperidol level for comparison. Thus the increased production and metabolic efficiency of this 1A4 enzyme may also have contributed to this inferred decrease in the haloperidol blood level. Kudo and Ishizaki 1999). even though the dosage had not been changed (Linnoila et al. it would likely have been greater than 4 ng/mL at baseline. and uridine 5′-diphosphate glucuronosyltransferase 1A4 (Bottiger et al. 2D6. When the phenytoin was added. Thus it appears that 3A4 is the P450 enzyme through which this interaction occurred.Neurology Case Vignettes 201 ing phenytoin (Dilantin). and phenytoin is an inducer of the glucuronidation 1A4 enzyme (Hachad et al. 3A4. Gibson et al. and phase II glucuronidation (Desai et al. 2C19. Although the specifics have not yet been well characterized. A trough haloperidol blood level drawn on admission was less than 2 ng/mL. Raucy 2003). The increase in the . 16. Discussion This is an example of an inducer added to a substrate. 1980). Chetty et al.

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

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

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

Ucar et al. 1999. 1999. however.Neurology Case Vignettes 205 visited a neurologist for evaluation and treatment. specifically including 1A2. she began to experience the familiar and dreaded sensation of evolving depression. her depressive symptoms had remitted. yet several other studies from 1997 onward strongly suggested that there is no increase in carbamazepine-10. The psychiatrist was aware that the presence of carbamazepine leads to significant reductions in lamotrigine blood levels. It also induces UGT1A4 (Arana 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. 1998.11-epoxide with the addition of lamotrigine (Besag et al. 1988. 2C9. 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. titrated to a dosage of 600 mg/day (blood level. 1992). 1996. 7. 2002). She quickly contacted her psychiatrist and informed him of her current clinical state. even though the lamotrigine dosage had not been decreased (Bottiger et al. as well as the recent addition of carbamazepine to her regimen. Rambeck et al. (She had tolerated carbamazepine in the past. Spina et al. The addition of carbamazepine led to the increased production of 1A4. Gidal et al. 1996. This decrease in the lamotrigine blood level likely led to the patient’s impending depression. and 3A4.11-epoxide metabolite. Lucas et al.5 µg/mL). which was therefore able to metabolize the lamotrigine more efficiently. 2B6. DeVane and Nemeroff 2002. 1998. Bottiger et al. Hachad et al. He prescribed carbamazepine (Tegretol). Parker et al. Faucette et al. A 1992 study suggested that this was the case (Warner et al. Accordingly. 1997). 1998. leading to a decrease in the blood level of lamotrigine. 2004. Within 3 weeks of achieving this new dosage. 2004). There is some debate as to whether the addition of lamotrigine to carbamazepine increases the production of the neurotoxic carbamazepine10. 1999). Carbamazepine is an inducer of multiple P450 enzymes. 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. Discussion This is an example of an inducer added to a substrate. . which proved quite effective for her pain. Lamotrigine is primarily metabolized through phase II glucuronidation.) One month after starting the carbamazepine. Miners and Birkett 1998. Eriksson and Boreus 1997. but it had proven ineffective for her moodrelated symptoms.

et al: Carbamazepine toxicity with lamotrigine: pharmacokinetic or pharmacodynamic interaction? Epilepsia 39:183–187. 1999 DeVane CL. Wang H. Ther Drug Monit 21:171–174. Pisani F. et al: Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-10. Berry DJ. Specht U. 1998 Miners JO. 2004 Warner T.11-epoxide during addition of lamotrigine treatment in children. Levy RH: New antiepileptic drugs: review on drug interactions. Clin Pharmacokinet 31:198–214. Drug Metab Dispos 27:605–612. Shaw R. Svensson JO. Gilfillan DJ. Br J Clin Pharmacol 45:176–178.206 Drug–Drug Interaction Primer References Arana GW. Molloy M. 1998 Bottiger Y. Hamilton GA. Prevett M. Nguyen N. Pritchard P. Clin Pharmacokinet 31:309–324. 1997 Hachad H. 1999 Lucas RA. 2004 Gidal BE. Prim Psychiatry 9:28–57. 1996 Spina E. Patsalos PN. Eur J Clin Pharmacol 59:879–882. et al: Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Birkett DJ: Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Ther Drug Monit 19:499–501. Rutecki P. Epilepsy Res 28:207–211. 1998 Rambeck B. Neuvonen M. Preston T. Stahle L: Lamotrigine drug interactions in a TDM material. Luurila H. Wolf P: Pharmacokinetic interactions of the new antiepileptic drugs. et al: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Epstein S. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Drug Metab Dispos 32:348–358. et al: Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test. 1992 . et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. 2002 Eriksson AS. 1988 Besag FM. 1996 Ucar M. Nemeroff CB: 2002 guide to psychotropic drug interactions. 2002 Hiller A. Br J Clin Pharmacol 45:525–538. 1998 Parker AC. Ther Drug Monit 24:91–103. J Clin Psychiatry 49:448– 449.11-epoxide. Bergstrom RF: A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism. Ragueneau-Majlessi I. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. et al: Effect of lamotrigine on carbamazepine epoxide/ carbamazepine serum concentration ratios in adult patients with epilepsy. Epilepsy Res 11:147–150. Strassburg CP. Pool F. 1997 Faucette SR. Eur J Clin Pharmacol 54:639–643. Boreus LO: No increase in carbamazepine-10.

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

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

As a result. 2004). The neurologist added carbamazepine (Tegretol). the patient’s depression had again remitted. 1995). the neurologist opted to discontinue the carbamazepine and start gabapentin (Neurontin). whereas lower parent-to-metabolite ratios predict poorer response (Golden et al. The carbamazepine did relieve the neuralgia pain.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). Hawke RL. 2001). Carbamazepine has been shown to drastically reduce levels of bupropion. bupropion is roughly twice as potent a norepinephrine reuptake inhibitor as hydroxybupropion (Jefferson et al. et al: Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. However. However. titrated to a dosage of 400 mg bid (blood level. and at least one study has demonstrated that higher parent-to-metabolite ratios predict better response. Lecluyse EL. et al: Evaluation of the contribution of cytochrome P450 3A4 to human liver microsomal bupropion hydroxylation. Within 6 more weeks. Bupropion is a substrate of P450 2B6 (Faucette et al. Shord SS. 2000. rise almost as much (Ketter et al. He developed trigeminal neuralgia and was referred to a neurologist to address this condition. 2005). no study has examined the clinical effects of these ratios when they are generated by coadministration of bupropion with a P450 2B6 inducer. 6 months later the patient experienced a resurgence of depressive symptoms.2 µg/mL). Thus. 2001 . 8. References Faucette SR. Drug Metab Dispos 28:1222–1230. although levels of the primary active metabolite. Discussion This is an example of an inducer added to a substrate. which proved as effective as the carbamazepine for treating the trigeminal neuralgia. hydroxybupropion. 2000 Faucette SR. 1988). Drug Metab Dispos 29:1123–1129.400 mg/day. but the available evidence strongly suggests that the addition of carbamazepine may undermine the antidepressant efficacy of bupropion. specifically including 2B6 (Faucette et al. Carbamazepine is an inducer of multiple P450 enzymes. Hawke RL. this case is somewhat theoretical and conjectural in nature. Prudent clinicians are advised to beware of this potential complication when combining these agents. eventually titrating to a total daily dosage of 2. However. this prompted the psychiatrist to confer with the neurologist. When he reported this depressive recurrence to his psychiatrist. 300 mg every morning.

Within a month. This led to a referral to a neurologist. II: the role of metabolites in clinical outcome. Discussion This is an example of an inducer added to a substrate. Pradko JF. who started her on mirtazapine (Remeron). and insomnia. Mirtazapine is a substrate of P450 1A2. Laizure SC. titrating to a dosage of 300 mg bid (blood level. Arch Gen Psychiatry 45:145–149. Drug Metab Dispos 32:348–358. et al: Carbamazepine but not valproate induces bupropion metabolism. Clin Ther 27:1685–1695. Hamilton GA. weight loss. She was referred to a psychiatrist. When carbamazepine was added to the mirtazapine. titrating to 30 mg/day. and 3A4 (Stormer et al. The psychiatrist compensated for this effect by doubling the previous dose of mirtazapine. Muir KT: Bupropion for major depressive disorder: pharmacokinetic and formulation considerations. 1998. who opted to start the patient on carbamazepine (Tegretol). including 1A2 and 3A4 (Arana et al. leading to a restoration of full antidepressant efficacy. a 66-year-old woman had developed new-onset major depression with prominent anxiety. 1988 . 1988. References Arana GW. DeVane CL. 7. Wang H. When she reported this to her psychiatrist. Roughly 1 year later. 2000). Spina et al. 2D6. 2000.210 Drug–Drug Interaction Primer Faucette SR. 1995 TRIGEMINAL TRIBULATIONS (II) In the context of multiple recent deaths of friends and family. One month later. resulting in a decrease in the blood level of mirtazapine and loss of antidepressant efficacy. this led to a significant increase in the amount of 1A2 and 3A4 that were available to metabolize the mirtazapine. Jenkins JB. et al: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. J Clin Psychopharmacol 15:327–333. the addition of carbamazepine results in a 60% decrease in mirtazapine blood levels (Timmer et al. One study indicates that on average. she had regained her prior level of antidepressant response with no ill effects. 1996. et al: Bupropion in depression. Timmer et al. Epstein S. 2000). et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. she experienced a near-remission of her symptoms. Molloy M. Schroeder DH. 2005 Ketter TA. 1988 Jefferson JW. she developed trigeminal neuralgia. 2004 Golden RN.7 µg/mL). Carbamazepine is an inducer of multiple P450 enzymes. Parker et al. Ucar et al. J Clin Psychiatry 49:448–449. 2004). even though the dosage had not been decreased. After 5 weeks. he performed some research and then proceeded to increase her mirtazapine dosage to 60 mg/day. the patient experienced a partial recurrence of her prior depressive symptoms.

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

et al: Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. An update. the patient became concerned that the friends of the men who assaulted him were monitoring him to find an opportunity to “finish the job. His delusions and hallucinations significantly decreased. this led to a significant increase in the amount of 3A4 that was available to metabolize the aripiprazole. 1988 Bristol-Myers Squibb: Abilify (package insert). resulting in a decrease in the blood level of aripiprazole and loss of efficacy as a mood stabilizer. Further collateral history from the family confirmed that these symptoms were longstanding. 2005 Spina E. He managed to locate a police officer. Once he was taken to the hospital. presumably as a delayed sequela of his assault. leading to a restoration of full efficacy as a mood stabilizer. titrated to 4 mg/day. Psychosomatics 46:262–273. leading to the diagnosis of schizophrenia. Within 2 months of starting phenytoin. and he was referred to a neurologist. Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine. Epstein S. 1996 Ucar M. Luurila H. 2005).” and he heard them making noises outside his door. even though the dosage had not been decreased (deLeon et al. although they did not remit entirely. One year later. The Abilify package insert cites a 70% decrease in aripiprazole blood levels when carbamazepine is added (Bristol-Myers Squibb 2005). a 33-year-old homeless man suffered a severe assault that included closed head injury. titrated to 400 mg/day (blood level. 16. Bristol-Myers Squibb. who then called an ambulance. Molloy M. Clin Pharmacokinet 31:198–214.212 Drug–Drug Interaction Primer carbamazepine was added to the aripiprazole. 2004 HOMELESS While trying to prevent his coat from being stolen. the surgical team discovered that he endorsed an array of paranoid delusions and auditory hallucinations. Princeton. Cozza KL: The dosing of atypical antipsychotics. Armstrong SC. Pisani F. 2005 deLeon J. et al: Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. The psychiatrist compensated for this effect by doubling the previous dosage of aripiprazole. J Clin Psychiatry 49:448–449. who started the patient on phenytoin (Dilantin). although they .4 µg/mL). Neuvonen M. he experienced his first generalized seizure. NJ. Eur J Clin Pharmacol 59:879–882. He was started on risperidone (Risperdal). References Arana GW. Several other seizures followed in the succeeding weeks.

Neurology Case Vignettes 213 were never there when he looked outside. 2003 ILLUSORY INTERACTION A 67-year-old man had been chronically treated with phenytoin (Dilantin). 2001 Gibson GG. Several months ago aspirin. Risperidone is a substrate of 2D6 and 3A4 (DeVane and Nemeroff 2001). Although his neurologist did not understand why his phenytoin level had declined. his paranoia and hallucinations had again largely abated. she increased the patient’s risperidone to 8 mg/day. 2002 Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Within 3 weeks. Psychosomatics 46:262–273.7 µg/mL) for a longstanding. 2005 DeVane CL. 1999 deLeon J.0 µg/mL. The next time his phenytoin level was checked. 1999). 18. 2002. Armstrong SC. tonicclonic seizure disorder. Rogers T. References Bork JA. was added to his regimen to address his coronary artery disease. specifically including 3A4 (Gibson et al. J Clin Psychiatry 60:469–476. this led to a significant increase in the amount of 3A4 that was available to metabolize the risperidone. he proceeded to raise the dosage to 700 mg/day to try to bring the . 500 mg/day (blood level. When he reported these concerns to his psychiatrist. generalized. J Clin Psychopharmacol 21:408–416. Cozza KL: The dosing of atypical antipsychotics. it had declined to 14. el-Sankary W. Plant NJ: Receptor-dependent regulation of the CYP3A4 gene. even though the dosage had not been decreased (Bork et al. Raucy 2003). 325 mg/day. resulting in a decrease in the blood level of risperidone and loss of antipsychotic efficacy. It is estimated that adding phenytoin to risperidone results in a roughly 50% decrease in blood levels. 2005). When phenytoin was added to the regimen. Toxicology 181–182:199–202. Wedlund PJ. 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. de Leon J: A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A. Discussion This is an example of an inducer added to a substrate. thus it has been suggested that one can compensate for this by doubling risperidone dosages after phenytoin has been added (deLeon et al. Nemeroff CB: An evaluation of risperidone drug interactions. Drug Metab Dispos 31:533–539. Phenytoin is an inducer of multiple P450 enzymes.

It was not the drug– . 1986). He then decreased the patient’s phenytoin dosage back to 500 mg/day and 1 week later obtained a total phenytoin level of 14. However.9 µg/mL. Paxton 1980). It would be tempting to conclude that because pure displacement drug– drug interactions. In fact.1 µg/mL. as this case illustrates. and analogous situations such as hypoalbuminemia. However. With the addition of aspirin to phenytoin.5 µg/mL (normal range. 1–2 µg/mL).214 Drug–Drug Interaction Primer level back to the higher part of the standard therapeutic range. After consulting with a colleague. Discussion This is an example of plasma protein binding displacement without accompanying metabolic inhibition. 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. when previous attempts at dosage titration had produced blood levels in the 22–26 µg/mL range. which was 2. and the total concentration actually decreases.” can pose real clinical problems for patients. and it is therefore completely safe to simply follow total concentrations. The patient’s symptoms had also abated by that time. Within 1 week. The addition of aspirin to phenytoin produced no change in the free phenytoin concentration and thus no phenytoin toxicity. this free fraction. the neurologist obtained a free phenytoin level. The patient had also demonstrated these symptoms many years ago. the free concentration is unchanged. in addition to being the pharmacologically active fraction of drug. and sedation. 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. Lim et al. nystagmus. the free fraction of phenytoin remains elevated. 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. Thus. when they interface with “standard practice. The net result of these processes is that once equilibrium is achieved. This produces elevations in the free fraction of both drugs. However. do not alter free concentrations. the level had risen to 19. this maneuver actually produced an iatrogenic case of mild phenytoin toxicity.2 µg/mL and free phenytoin level of 1. but the patient had developed a new tremor. pure displacement interactions. Aspirin and phenytoin are both highly plasma protein–bound drugs (Kodama et al. because aspirin does not in any way inhibit the metabolism of phenytoin. 2000. then there can be no situation in which they become clinically significant. is also the fraction that is available for clearance. there is mutual displacement from plasma protein binding sites between aspirin and phenytoin.

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

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

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

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

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

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

soon thereafter she experienced a cardiac arrest and expired despite efforts at resuscitation (R. March 15. In this case.us. Unfortunately. After conferring with her previous psychiatrist. titrating to a dosage of 150 mg qhs. in full remission. Accessed July 29. and she experienced a recurrence of her depression as a consequence of her current disability. J Clin Pharmacol 38:106–111. Her previous depressive episodes had responded to amitriptyline (Elavil). Bertz RJ. and this was providing adequate analgesia. her surgeon ordered two successive doses of haloperidol (Haldol). 2002 STRUCTURAL SIMILARITIES AND CARDIAC CALAMITIES A 55-year-old woman with a history of major depressive disorder. the patient became increasingly confused. She was. and a seizure. She was also receiving hydromorphone to treat her postsurgical pain. et al: Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. according to Piscitelli et al. Greenblatt DJ. the decreased meperidine led to less effective analgesia. fell from a ladder while mending a shingle on her house and fractured her hip. Kress DR. August 2002). Love. Grassi JM. although she had not taken this medication for more than 8 years. so the surgeon added cyclobenzaprine (Flexeril). however. et al: The effect of ritonavir on the pharmacokinetics of meperidine and normeperidine.html. personal communication. the surgeon started the patient on amitriptyline. [2000]). 200 mg/day. tremor. 10 mg tid. . Pharmacotherapy 20:549–553.222 Drug–Drug Interaction Primer tion of meperidine into the normeperidine metabolite. Available online at http://www3. von Moltke LL. She eventually became frankly combative and required restraints. 2000 von Moltke LL. in order to help calm her. 5 mg intramuscularly. At this point. Over the next week. with alternating periods of somnolence and increasingly severe agitation and irritability. while the increased normeperidine led to emerging dysphoria.com/WOW/op024. Clin Pharmacol Ther 67:335–341. irritability. References Greenblatt DJ.elsevierhealth. Harmatz JS. 1998 Wong: Wong on Web Paper: Notes on Meperidine. leading to decreased blood levels of meperidine and increased blood levels of normeperidine (normeperidine’s area under the curve is increased by 47%. She was hospitalized for a sustained period. 2000 Piscitelli SC. complaining about muscle stiffness and cramping. 2002. roughly 3 hours apart. et al: Alprazolam-ritonavir interaction: implications for product labeling.

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

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

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

Parker RM: The Libby Zion Case: one step forward or two steps backward? N Engl J Med 318:771–775. although the patient reported compliance with the lithium. Lynch T. titrated rapidly to a dosage of 4 mg/day. 1995 Sporer KA: The serotonin syndrome: implicated drugs. Although he did not understand why the lithium level had declined. 50 mg tid. The patient eventually had his dosage of lithium titrated to 750 mg/day. This case mirrors the famous Libby Zion case. et al: Serotonin syndrome. Zion. culminating in an acute central serotonin syndrome (Sporer 1995). References Asch DA. with a blood level of 0. She developed a fever of 107. who was regularly taking phenelzine. 1. the psychiatrist and patient both felt more comfortable transitioning from divalproex to lithium. Four weeks after the indomethacin had been discontinued. Three months later. Drug Saf 13:94–104. . he nonetheless increased the lithium dosage to 1. 81 µg/mL). the patient’s liver function tests (γ-glutamyltransferase and alanine transaminase) rose to more than double their baseline values. and euthymia was restored.250 mg/day (blood level. Lewis L. for persistent tendinitis.9 mEq/L.226 Drug–Drug Interaction Primer property of meperidine led to a rapid increase in synaptically available serotonin. the patient’s tendinitis had resolved and his orthopedist felt that he should taper and discontinue the patient’s indomethacin. the combination of these two agents led to an acute and severe accumulation of serotonin. pathophysiology and management. and because phenelzine inhibits the breakdown of all monoamines (including serotonin). 1995 ORTHOPEDIC RECOVERY AND MANIC RECURRENCE A 27-year-old squash player with bipolar I disorder was being treated with divalproex sodium (Depakote). when he also began taking chronic indomethacin (Indocin).6°F and died within 6 hours of her arrival in that hospital (Asch and Parker 1988). Neurology 45:219– 223. His psychiatrist had a lithium level checked immediately and to his surprise found that it was only 0. Although this need not have necessitated the discontinuation of divalproex. received meperidine in an emergency room for shaking chills. He rapidly responded to these interventions.4 mEq/L. The patient’s new lithium level was 0.200 mg/day and added risperidone (Risperdal). and his divalproex was tapered and discontinued. the patient began to experience the emergence of manic symptoms.9 mEq/L. After 1 month on this regimen. 1988 Bodner RA. in which Ms.

As mentioned in “The Tremulous Triathlete” case in Chapter 2. Clin Pharmacokinet 29:172–191. Therefore. the patient’s kidneys were able to more efficiently excrete the lithium. The proposed mechanism for this interaction is that NSAIDs inhibit prostaglandin synthesis in the kidney.9 mEq/L. 1997 Ragheb M: The clinical significance of lithium–nonsteroidal anti-inflammatory drug interactions. will often elevate lithium blood levels (Finley et al. 1995 Imbs JL. J Clin Psychopharmacol 10:350–354.200 mg/day. the lithium blood level of 0. Therefore. so close observation and frequent lithium levels are warranted. 1997). The psychiatrist eventually compensated for this effect by increasing the lithium dosage to 1. et al: Mechanisms of drug interactions with renal elimination of lithium (in French). Danion JM. lithium is entirely renally excreted. The change in lithium blood level can be quite variable and difficult to predict.4 mEq/L and a subsequent vulnerability to a manic switch. at a dosage of 750 mg/day. References Finley PR. The indomethacin was already present when the titration to a therapeutic dose and blood level of lithium occurred. was higher than it would have been had the indomethacin not been present. with the discontinuation of the indomethacin. leading to a decrease in the lithium level to 0. and therefore a variety of medications that alter renal function can alter the rate of lithium excretion. with the exception of aspirin and sulindac (Clinoril). Peabody CA: Clinical relevance of drug interactions with lithium. Ragheb 1990). All nonsteroidal antiinflammatory drugs (NSAIDs. Barthelmebs M. 1990 . and the addition of risperidone also helped to restabilize the patient. Warner MD. Bull Acad Natl Med 181:685–697.Surgery/Anesthesia Case Vignettes 227 Discussion This is an example of reversal of inhibition. 1995. including indomethacin). thus interfering with the excretion of lithium (Imbs et al.

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

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

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

When she was consulted. with no increase in his generalized anxiety. the psychiatrist then instructed the patient to increase his buspirone by 5 mg/day until he resumed his usual dosage of 30 mg/day. After the patient completed the itraconazole regimen. this significantly impaired the ability of 3A4 to efficiently metabolize the buspirone. When the itraconazole was added. NJ. and by azole antifungal agents. Montvale. Discussion This is an example of an inhibitor added to a substrate. 17. Lamberg TS. 1997) for the second round of itraconazole therapy. et al: Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine. This led to the symptoms of sedation. The patient followed these instructions faithfully. even though the buspirone dosage had remained constant during the first week of itraconazole therapy. 1997 von Moltke LL. et al: Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole. nausea. When he reported these events to his psychiatrist. norfluoxetine. and itraconazole is a strong competitive inhibitor of 3A4 (von Moltke 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.to 13-fold) (Kivisto et al. resulting in a large increase in the blood level of buspirone.232 Drug–Drug Interaction Primer the itraconazole regimen. J Clin Pharmacol 36:783–791. 2002 Kivisto KT. However.3 µg/mL). and during the second round of itraconazole he experienced only mild drowsiness. 1996 NYSTAGMUS A 32-year-old woman with a long-standing seizure disorder was doing well with phenytoin (Dilantin). References Janssen Pharmaceutica: Sporanox (package insert). These symptoms persisted for almost a week after completion of the first week of itraconazole. Schmider J. she had been experiencing symptoms consistent with premenstrual dyspho- . she instructed him to decrease his buspirone dosing by 5 mg/day until he reached a dosage of 5 mg/day. Kantola T. Greenblatt DJ. Clin Pharmacol Ther 62:348– 354. Janssen Pharmaceutica. and tremor. Buspirone is a 3A4 substrate (Kivisto et al. She instructed him to begin this buspirone taper on the first day of the second round of itraconazole. 1996). 1997). 300 mg/day (blood level.

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

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

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

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

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

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

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

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

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

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Used with permission. Armstrong SC. Armstrong. 2005. and it should precede the quest for efficacy. Kelly L. Copyright 2005. 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. another domain of psychopharmacology is critical to best practice. 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. Scott C. M.Appendix A AN OVERVIEW OF PSYCHOTROPIC DRUG– DRUG INTERACTIONS Neil B. Cozza KL: “An Overview of Psychotropic Drug-Drug Interactions.D. Sandson. Cozza. M. The Academy of Psychosomatic Medicine. To para- This appendix is reprinted from Sandson NB. The array of available psychopharmacologic agents has expanded tremendously over the last 20 years. It is a formidable challenge to remain familiar with the evolving evidence base. The growing range of treatment options has made treating patients more complex.” Psychosomatics 46:464–494. M. However. 243 .D.D.

TYPES OF DRUG–DRUG INTERACTIONS The two major varieties of drug–drug interactions are pharmacodynamic interactions and pharmacokinetic interactions. and other related difficulties. including alterations in drug metabolism. it is incumbent on clinicians to “First.16 However. this wide range presents an overwhelming flood of information. . They often promote a therapeutic paralysis that is almost as undesirable as an ignorance of drug–drug interactions. which results from the combination of a monoamine oxidase inhibitor (MAOI) with a selective serotonin reuptake inhibitor (SSRI).5. the synergistic anticholinergic activity of amitriptyline combined with benztropine can produce constipation. There are some excellent publications on this topic.18.9–11 Yet. absorption. for many psychiatrists. Drug–drug interactions are actually quite commonplace1–5 and are responsible for considerable patient morbidity and mortality. This review focuses on intrapsychotropic drug–drug interactions involving antidepressants.13 However. This disconnection is explained. excretion. urinary retention. do no harm. in part. antipsychotics. For example.4. Grappling with the entire array of drug–drug interactions is a worthwhile goal for anyone who prescribes medications.” Unfortunately. as understanding of the importance of drug–drug interactions grows.17 Another familiar example is central serotonin syndrome. and mood stabilizers. one agent causes the blood level of another agent to be raised or lowered. but it can be a daunting enterprise. An ideal starting point for psychiatrists is to examine drug–drug interactions involving the familiar psychotropic agents that are most relevant to their practices. and distribution. especially where drug–drug interactions are concerned. treatment failures. Pharmacokinetic drug– drug interactions may occur through multiple mechanisms.15. and subsequent health care costs.19 In pharmacokinetic interactions. by our relatively primitive ability to detect drug–drug interactions. drug–drug interactions are rarely foremost in the minds of otherwise excellent clinicians.6–8 A growing and sobering evidence base implicates drug–drug interactions as a major contributor to hospital admissions.12. which appropriately examine the issue of drug–drug interactions across medical disciplines. Most current drug–drug interaction software programs have problems with both sensitivity and specificity14 and are not especially user friendly. heat stroke. avoidable medical complications. Pharmacodynamic interactions represent the synergy or antagonism of each drug’s effects at target receptors. concerned physicians are eager to know more. practitioners often fall well short of that dictum.244 Drug–Drug Interaction Primer phrase Hippocrates.

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

28 Distribution issues are actually somewhat infrequent for psychotropics. P-glycoprotein inducers increase the amount of active P-glycoprotein and thus lead to more extrusion and excretion of P-glycoprotein substrates. Alterations in gastrointestinal pH.26 Drugs that affect renal excretion can alter the blood level of lithium. P-glycoprotein inhibitors antagonize this process and lead to greater retention and absorption of P-glycoprotein substrates. and inducers. It also lines the capillaries of the blood-brain barrier. and P-glycoprotein inducers decrease the levels of P-glycoprotein substrates. P-glycoprotein is an ATP-dependent. P-Glyco- . the absorption of ziprasidone is much greater when it is consumed with food. excretion. and in this location it is an important regulator of drug absorption and bioavailability. UGTs. the presence or absence of food. although the blood level of unbound or free valproate can be significantly increased by daily antipyretic doses of aspirin.29. For instance. Like the P450 and UGT metabolic systems. the P-glycoprotein transporter is emerging as a critically important contributor. and distribution. extruding transporter. OTHER PHARMACOKINETIC PROCESSES Other pharmacokinetic drug–drug interactions are caused by alterations in absorption (not relating to P-glycoprotein). UGT. The net effect of this activity is that Pglycoprotein inhibitors increase the blood levels of P-glycoprotein substrates. the P-glycoprotein transporter has substrates. P-glycoprotein is also found in the cells lining renal tubules. The list of known 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.30 CURRENT PRACTICAL RESOURCES Tables of drug–drug interactions involving the P450.27. inhibitors. and P-glycoprotein systems are available from multiple published and online sources.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 the rate of bowel motility are only a few of the factors that can affect absorption. P-glycoprotein functions by extruding substrates from the cytosol of enterocytes back into the gut lumen. It resides in the plasma membrane of enterocytes that line the gut lumen. or from the capillaries of the blood-brain barrier back into the bloodstream. and inducers is already quite large and is growing with each passing month.

38 Fluoxetine (norfluoxetine).15. provides an excellent P450 table online at http:// medicine. 2nd Edition.47. M. 56..com/Cytochromes. Fluoxetine and its active metabolite norfluoxetine are together metabolized by P450 2C9.mhc.D.D. as well as very complete UGT and P-glycoprotein tables. Sertraline and its mildly active metabolite desmethylsertraline are substrates of multiple P450 enzymes. M. and 3A4. much like cimetidine.43.An Overview of Psychotropic Drug–Drug Interactions 247 proteins.51 It is also both a substrate and an inhibitor of P-glycoprotein. 2D6. Paroxetine is primarily metabolized by P450 2D6 and secondarily by 3A4. At doses above 150 mg/day.41.54.45. David Flockhart.57 Sertraline inhibits 2D6 in a dose-dependent manner.D (American Psychiatric Publishing. 2B6. which contains a P450 table tailored for psychiatrists.47 Fluvoxamine. 2D6.iupui. Fluvoxamine is primarily metabolized by P450 1A2 and secondarily by 2D6.42.49 It is a pan-inhibitor like fluoxetine.35 Citalopram is a substrate of P-glycoprotein. Citalopram is metabolized primarily by P450 2C19. It is also a P-glycoprotein inhibitor.47 Sertraline.40 and mildly to moderately inhibit 1A2. and 3A4..50 and a mild to moderate inhibitor of 2B6. It is a potent inhibitor of 1A2 and 2C19. www. 2C9. 2C19. Oesterheld is the coauthor of a website. 2C9.31.48. 2C19.34 as evidenced by its ability to increase blood levels of desipramine and metoprolol. 2D6 inhibition may become .edu/flockhart/. and3A4.D. The pharmacokinetic features of escitalopram are basically the same as those of citalopram. Scott Armstrong.44 It is also both a substrate and an inhibitor of P-glycoprotein.52 Paroxetine. by Kelly Cozza.41–46 Fluoxetine can reasonably be considered a P450 pan-inhibitor. M. they potently inhibit 2D634. At doses under 100 mg/day.45. and Jessica Oesterheld.55 but only a mild inhibitor of other P450 enzymes.37. 2D6.31–33 It is likely a mild to moderate inhibitor of 2D6.53 It is a potent inhibitor of 2B6 and 2D6 34.34. 2003).36 Escitalopram. Dr.50. and 3A4. sertraline may only mildly inhibit 2D6. SPECIFIC PHARMACOKINETIC FEATURES OF PSYCHOTROPIC AGENTS Antidepressants SSRIs Citalopram.39 Together... Inc. M.42.45. 48.

90 MAOIs. clomipramine.20. Mirtazapine has multiple metabolic pathways. and 2E1. and 3A4.248 Drug–Drug Interaction Primer moderate to potent. Bupropion is primarily metabolized by P450 2B6. sertraline also appears to be a specific and potent inhibitor of UGT1A4. and nortriptyline has been demonstrated to be a P-glycoprotein substrate.41.93 (a minor P450 enzyme) and a mild to moderate inhibitor of 1A2. Secondary-amine tricyclic antidepressants (TCAs). trimipramine. tends to be only mild.34.79 Tertiary-amine TCA inhibition of 2D6. and doxepin.62 Sertraline is also a P-glycoprotein inhibitor. 2C19.87 Mirtazapine. 23.18. The metabolism of tertiary-amine TCAs.89 It has no significant inhibitory or inductive capabilities.86.47 Tricyclic Antidepressants Secondary-amine tricyclic antidepressants.80. Tertiaryamine TCAs undergo both demethylation to secondary amine TCAs through the action of 1A2.63.73– 77 UGT1A4 also makes a minor contribution to the metabolism of tertiary amine TCAs.37.69–72 Tertiary-amine TCAs.68 These TCAs also appear to be both substrates and inhibitors of P-glycoprotein.85 Duloxetine.83 It is a moderate to potent inhibitor of 2D6.88. and protriptyline. as evidenced by the ability of 25 mg/day of sertraline to double the blood level of lamotrigine. which performs hydroxylation on these compounds. 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 3A4.91 Tranylcypromine is also a substrate of MAOA.82. nortriptyline.69–71.78.65.91 but it is also a potent inhibitor of P450 2A692. including metabolism by P450 1A2. considered without the contribution of the secondary-amine metabolites.21.59–61 Possibly unique among the SSRIs.68 These TCAs also appear to be inhibitors of P-glycoprotein. and 3A4 and hydroxylation by 2D6.86 It is a moderate inhibitor of 2D6.84.34.67. 2D6.63–66 They are also moderate 2D6 inhibitors.19.81 Other Antidepressants Bupropion. 2C19. including amitriptyline. Duloxetine is metabolized by P450 1A2 and 2D6. imipramine. are primarily substrates of P450 2D6. including desipramine.94 . is much more complex than that of the secondary-amine TCAs.58 Sertraline is also a moderate inhibitor of 2B6 and 2C1942. and there is some evidence that amitriptyline and imipramine are mild inhibitors of 2C19.

trazodone relies primarily on P450 3A4 for its metabolism. 116 Haloperidol is also a P-glycoprotein inhibitor. 118 It lacks any known inhibitory or inductive capabilities. they appear to be P-glycoprotein inhibitors.119–122 .101 Trazodone. it is initially an acute inhibitor and later a chronic inducer. and it is a mild 2D6 inhibitor. this agent has a relatively low therapeutic index.109 Most of these agents display moderate to potent 2D6 inhibition. Atypical Antipsychotics Aripiprazole. Nefazodone is primarily metabolized by P450 3A4 into three major metabolites.52. As a general rule. a partial dopamine agonist.112.115 Pimozide. partial serotonin agonist that relies on 2D6 for its metabolism.An Overview of Psychotropic Drug–Drug Interactions 249 Nefazodone.107.101 Venlafaxine.117 It is also an inhibitor of P-glycoprotein.96 an acutely anxiogenic.110.79.111 As a class.108 3A4 makes only a minor contribution to the metabolism of most phenothiazines.103–107 with frequent contributions from 1A2 and phase II metabolism. phenothiazines are metabolized primarily by P450 2D6.114 It appears to be an in vitro P-glycoprotein substrate of weak affinity.67 It is also both a substrate and a mild inhibitor of P-glycoprotein. with a secondary contribution by 1A2. of P-glycoprotein.103.102 Trazadone is also an inducer of P-glycoprotein. displays more avid binding to the dopamine D2 receptor than any other antipsychotic.100 Also. with secondary contributions from 2D6 and 1A2. Haloperidol’s metabolism is quite complex.115 One of haloperidol’s metabolites is a potent 2D6 inhibitor. Like nefazodone. relying principally on P450 3A4 and phase II metabolism (not yet elucidated).52. Aripiprazole’s metabolism is roughly equally divided between P450 2D6 and 3A4. Venlafaxine’s metabolism relies primarily on P450 2D6.95 One of these is metachlorophenylpiperazine (mCPP). This agent.47 Antipsychotics Typical Antipsychotics Phenothiazines.117 It is a potent inhibitor of 2D6 and moderate inhibitor of 3A4.23. and one of the principal metabolites resulting from its metabolism by 3A4 is mCPP. although several typical agents are P-glycoprotein substrates as well.113 Haloperidol.106.112. Pimozide is metabolized primarily by P450 3A4.46.97–99 Nefazodone is a potent inhibitor of 3A4.80 Because of its arrhythmogenic potential.

with P450 3A4 serving as a secondary pathway. 128. 2D6.138–140 It is also likely an inhibitor of 2C19.141–143 Carbamazepine is a potent inducer of 3A4. 2B6. 2C8/9.112 It is also a known mild inhibitor of 2D6. Clozapine is principally metabolized by P450 1A2 with numerous secondary pathways. not yet well characterized. Olanzapine is mostly metabolized by P450 1A2 and UGT 1A4. including 2C9/19.137. Quetiapine is mostly metabolized by P450 3A4. In healthy adults.146–149 Lamotrigine Lamotrigine is primarily metabolized by UGT1A4. serve as a secondary pathway.22.127 It is also an in vitro Pglycoprotein substrate of low to moderate affinity112 and a P-glycoprotein inhibitor. Most of risperidone’s metabolism occurs through P45 2D6.250 Drug–Drug Interaction Primer Clozapine. although its inhibitory capability is unlikely to be clinically significant. and phase II metabolism (UGT 2B7) serve as minor pathways. 26.135–137 It is both a substrate and an inhibitor of P-glycoprotein.150 In the presence of a UGT1A4 inhibitor such as valproate. 2C8/9. as evidenced by carbamazepine’s ability to increase blood levels of both phenytoin and clomipramine.123–125 It appears to be an in vitro P-glycoprotein substrate of weak affinity.134. 2B6.129 It is also an in vitro P-glycoprotein substrate of moderate to strong affinity 112 and a P-glycoprotein inhibitor. although 3A4 also makes a significant contribution.23 although one or more P450 enzymes.145 and it also induces 1A2.111. 23. 2E1.50. 130–132 It is also an in vitro P-glycoprotein substrate of moderate to strong affinity.133 Ziprasidone. ziprasidone is principally metabolized by aldehyde oxidase.52 Quetiapine.134 It lacks any known inhibitory or inductive capabilities. with 2D6 serving as a minor pathway. Mood Stabilizers Carbamazepine Carbamazepine is primarily metabolized by P450 3A4.111.144.126 This agent has a fairly low therapeutic index. and UGT1A4.52 Risperidone. 112 Risperidone acts as a mild to moderate 2D6 inhibitor. this P450 pathway leads to the generation of toxic metabolites. a greater proportion of lamotrigine is metabolized through this P450 metabolic . although 1A2. and UGT 1A3/4. However. 3A4. Olanzapine.

167 and a mild inducer of 3A4.152 Oxcarbazepine is a mild inducer of 3A4.156 with minor contributions from multiple UGT1A family enzymes.169 Valproate Valproate’s metabolism is exceedingly complex. 1A9.164 It is likely to be a P-glycoprotein substrate.151.141 Phenytoin Phenytoin is primarily a substrate of P450 2C9 and 2C19. and UGTs 1A1 and 1A4. and 2B15.11-epoxide). 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.147.174. UGT1A6. Both oxcarbazepine and MHD are metabolized in part through phase II glucuronidation.157 It is also a P-glycoprotein substrate.An Overview of Psychotropic Drug–Drug Interactions 251 pathway. leading to production of these toxic metabolites. 3A4.158 It induces multiple enzymes. involving multiple phase I and II pathways (P450 2A6 and 2C9170.171 as well as epoxide hydrolase.155. 1A9. Its hepatic metabolism is mostly governed by phase II enzymes with a minor phase I contribution.149.159–162 Topiramate Topiramate is primarily renally excreted.168.163.173 It also inhibits multiple UGTs. including 2B6.170 .175 It is unclear if valproate has any meaningful inductive capabilities. 2C9/19. even when low dosages of lamotrigine are used. with no hepatic metabolic component.154 MHD is an inhibitor of 2C19. neither of which has been well characterized. 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. Some weak autoinduction (at UGT1A4) has been noted.149. Oxcarbazepine Oxcarbazepine is quickly metabolized to an active monohydroxyoxcarbazepine (MHD) metabolite by the action of arylketone reductase. 2B7. including 1A4.165 It is an inhibitor of 2C19166.141. It lacks any inhibitory or inductive capabilities. and 2B7171) as well as β-oxidation.151 Lithium Lithium is purely renally excreted.137.172 It is a moderate inhibitor of 2C9.153 and a moderate inducer of UGT1A4. the enzyme that metabolizes the principal metabolite of carbamazepine (carbamazepine-10.

179 However. etc. they are often involved as inducers of the metabolism of other agents. they also make it clear that the broad range of information on drug–drug interactions severely tests the limits of human recall.176 Table A–2 lists significant drug–drug interactions involving antipsychotics and other psychotropic agents. We urgently need programs . such as tobacco (smoked) and oral contraceptives containing ethinylestradiol. create drug– drug interactions with numerous psychotropic agents. caffeine. who will be harmed by drug–drug interactions. along with some drug–drug interactions involving other psychotropic agents (anxiolytics. the combination of lithium and haloperidol can produce an encephalopathic state. In all of these drug–drug interactions tables. Some ubiquitous nonpsychotropic agents/influences. Because several of these agents are anticonvulsants. in which substrate blood levels are increased. For instance. Although reviews such as this one may prove helpful to the clinician. selected examples of such interactions have been included in Table A–4. only those interactions that are both reasonably frequent and problematic are included.182 By virtue of their special importance. recognition that the clinician cannot be expected to remember all of these details is small consolation to our patients.178.181 and between acetylsalicylic acid and valproate. In contrast. It is simply not practical to insist that memorization of all the permutations of drug–drug interactions become the standard of care. Lithium and valproate are notable exceptions to this generalization.177 and lithium plus fluoxetine can yield a central serotonin syndrome. For instance.252 Drug–Drug Interaction Primer DISCUSSION Table A–1 lists significant drug–drug interactions involving antidepressants and other psychotropic agents.180 Hence. none of these drug–drug interactions are included in the tables. the antipsychotic agents generally play the role of substrates in substrate-inhibitor and/or substrate-inducer pairings. 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.). However. The only reasonable approach lies in the realm of computers. “Classic” drug–drug interactions include those between lithium and diuretics28. In general. 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. In these interactions. both of these combinations are common and well tolerated the vast majority of the time. these interactions involve substrate-inhibitor pairings. Table A–3 lists significant drug–drug interactions involving mood stabilizers and other psychotropic agents.

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

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276 TABLE A–1.86. Significant drug–drug interactions involving antidepressants Antidepressant and interacting drug Bupropion Carbamazepine Duloxetine Pharmacokinetic results Decreased level of bupropion192.147 Inhibition of P450 2D6 by bupropion84. Theoretical concern fatigue. sedation.83 Inhibition of P450 2B6 by fluvoxamine42.98 Clinical consequences Comments Fluoxetine Possible loss of therapeutic efficacy Dry mouth.83 Decreased metabolism of norepinephrine by MAOIs. constipation.193 Increased level of duloxetine Increased level of bupropion85 Increased level of bupropion85 n/a Mechanisms Induction of P450 2B6 by carbamazepine83.85 Theoretical concern Potentially fatal Drug–Drug Interaction Primer Nefazodone Increased level of metachlorophenylpiperazine (mCPP) Acute dysphoric anxiety Theoretical concern .19. increased sweating Increased risk of seizures Theoretical concern Fluvoxamine MAOIs Increased risk of seizures Increased risk of hypertensive crisis18. combined with norepinephrine reuptake inhibition by bupropion Inhibition of P450 2D6 by bupropion84.87 Inhibition of P450 2B6 by fluoxetine plus norfluoxetine42.

83 Inhibition of P450 2D6 by bupropion84.195 Combination of bupropion with mesoridazine or thioridazine can increase arrhythmogenic potential Possible loss of therapeutic Theoretical concern.198 277 .64.197.84.134.147 Inhibition of P450 2B6 by sertraline42.33.37. 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. efficacy but likely Increased risk of seizures Theoretical concern Increased arrhythmia risk and anticholinergic symptoms Possible loss of therapeutic efficacy Citalopram.103.137.75.65. 145.194 Mechanisms Inhibition of P450 2B6 by paroxetine42.107 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 TCAs84.104.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.85 Induction of P450 2B6 by phenytoin83.83 Inhibition of P450 2D6 by bupropion21. escitalopram Carbamazepine Decreased levels of citalopram and of escitalopram196 Induction of P450 3A4 by carbamazepine32.

38 Comments Potentially fatal Citalopram.103.107 Clinical consequences Central serotonin syndrome18.104.35. combined with serotonin reuptake inhibition by citalopram and by escitalopram Inhibition of P450 2D6 by citalopram and by escitalopram31.19.278 TABLE A–1. 159–161.34.33. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pharmacokinetic results Mechanisms Decreased metabolism of serotonin by MAOIs. 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 phenytoin32.198 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 .

34. by fluvoxamine34. Theoretical concern fatigue.40. increased sweating Possible loss of therapeutic Theoretical concern Induction of P450 1A2 by efficacy carbamazepine37.87 Clinical consequences Comments Secondary-amine Increased levels of TCAs secondary-amine TCAs35.86 fatigue. constipation.86 increased sweating Inhibition of P450 1A2 >> 2D6 Dry mouth.64. sedation. constipation.38 Duloxetine Bupropion Increased level of duloxetine Carbamazepine Fluoxetine. 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 pimozide35.86.195 Inhibition of P450 2D6 by bupropion84.38 Increased arrhythmia risk Theoretical concern and anticholinergic symptoms Dry mouth.37. increased sweating 279 .31.146 Inhibition of P450 2D6 by Dry mouth. or by paroxetine34. 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 escitalopram21.54.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.48. fluoxetine plus norfluoxetine fatigue. sedation. constipation. sedation.

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 crisis18.65.86.75.87 by MAOIs. paroxetine Inhibition of P450 2D6 by Increased EPS and other Combination of duloxetine86.195 Increased arrhythmia risk and anticholinergic symptoms Drug–Drug Interaction Primer TCAs Increased levels of TCAs87 .19. combined with serotonin and norepinephrine reuptake inhibition by duloxetine See information for interaction See information for of duloxetine and fluoxetine.107 side effects duloxetine with mesoridazine or thioridazine can increase arrhythmogenic potential Inhibition of P450 2D6 by duloxetine21.64. interaction of duloxetine paroxetine and fluoxetine.104.103.280 TABLE A–1.

135. sedation.83 Inhibition of multiple P450 enzymes (3A4. constipation. 86 Clinical consequences Increased risk of seizures Comments Theoretical concern Carbamazepine Ataxia.46.44. Clozapine Increased level of clozapine201 Increased sedation.123. 2C9/19. 40. 1A2. 2B6. dysarthria. 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. sedation. fatigue. Clozapine levels typically increase by roughly 50% with this combination Duloxetine Increased level of duloxetine87 Dry mouth.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1. seizure risk. and 3A4.40.60.60.112 (weak contribution) by fluoxetine plus norfluoxetine Inhibition of P450 2D6 by fluoxetine plus norfluoxetine34. diplopia. etc.34. 43.200 and P-glycoprotein47.138 by fluoxetine plus norfluoxetine Inhibition of P450 1A2. increased sweating 281 .46. etc. anticholinergic symptoms. 2D6. 2C9)41–43.124 as well as P-glycoprotein47. tremor. nausea.41.

etc.40.68. ataxia. dysarthria.158 by fluoxetine plus norfluoxetine Inhibition of P450 1A2 and 3A4 by fluoxetine plus norfluoxetine (probably)41. tremor.60 Inhibition of P450 2D6/ 3A434.46.130 and P-glycoprotein47. combined with serotonin reuptake inhibition by fluoxetine plus norfluoxetine Inhibition of P450 2D6 by fluoxetine plus norfluoxetine34.44.156 and P-glycoprotein47. 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 .98 Inhibition of both P450 2C9/19 43.282 TABLE A–1. nausea.155.46. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pharmacokinetic results Mechanisms Decreased metabolism of serotonin by MAOIs. Increased EPS and One known case arrhythmogenic potential of serious bradycardia205 EPS.112 by fluoxetine plus norfluoxetine Clinical consequences Central serotonin syndrome178.97.60.40.202 Comments Potentially fatal Fluoxetine (continued) MAOIs n/a Nefazodone Increased level of mCPP203 Increased level of phenytoin204 Acute dysphoric anxiety Phenytoin Nystagmus.

41.208 by fluoxetine plus norfluoxetine Inhibition of multiple P450 Increased EPS and other enzymes (1A2. sedation. 283 .83 1) Inhibition of multiple P450 1) Increased level of enzymes (3A4.206.60.138 by fluvoxamine.51.40.43. thioridazine.75.200 of fluvoxamine and P-glycoprotein47.46.112 by fluoxetine plus norfluoxetine Combining with mesoridazine.64. symptoms 70.52. carbamazepine211.207 Mechanisms Clinical consequences Comments Typical antipsychotics Increased levels of most typical antipsychotics194. diplopia.209 Inhibition of multiple P450 Increased arrhythmia risk enzymes21.46. 2D6.50.47.69. etc. 2) induction of P450 1A2 by carbamazepine48.60. 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. and side effects 3A4)34. tremor.45.212 and 2) decreased level 2C9)42.44.41. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug TCAs Pharmacokinetic results Increased levels of TCAs20. 1A2.135. 2B6. nausea. dysarthria.103–105.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.146 Increased risk of seizures Ataxia.40.107.43.48.34.210 and P-glycoprotein47. and anticholinergic 75–77 and P-glycoprotein36.52.

2C9/19.88.to 2D6 (weak) and 3A4.86 fatigue.123.50.52. syndrome18. This combination can 2D6. sedation.112 etc. by fluvoxamine Inhibition of P450 1A2 >> 2D6 Dry mouth.19. fourfold tein (weak contribution)47.50.284 TABLE A–1. by fluvoxamine34.48. constipation. increase three. seizure risk. increased sweating Potentially fatal Decreased metabolism of Central serotonin serotonin by MAOIs.89 syndrome219 levels by as much as fourfold Drug–Drug Interaction Primer .48.34.45.124 as well as P-glycoprosymptoms. anticholinergic 51. Increased sedation.217 combined with serotonin reuptake inhibition by fluvoxamine Inhibition of P450 1A2.37. Somnolence (perhaps). and 3A4 by increased risk of serotonin increase mirtazapine fluvoxamine34.48. 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.

210.47. symptoms 63.45. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Olanzapine Pharmacokinetic results Increased level of olanzapine127.52.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.48.48.50.47.225 and P-glycoprotein by fluvoxamine34.65.50.52.208 Tertiary-amine TCAs Typical antipsychotics Increased levels of Inhibition of multiple P450 Increased EPS and other most typical enzymes (1A2.112. 2D6.47.117 arrhythmogenic potential Inhibition of both P450 2C9/19 Nystagmus.52.47.52.155. dysarthria. 2D6 (weak).48. and P-glycoprotein by sedation. thioridazine.36. 107.50. or pimozide can increase arrhythmogenic potential 285 .103–105.156.223.73–77.112.210 Combining with mesoridazine. nausea. ataxia.222 Increased levels of tertiary-amine TCAs75.158 tremor. and 3A4) side effects antipsychotics194. etc. risk and P-glycoprotein by of EPS fluvoxamine34.220 Mechanisms Clinical consequences Comments Pimozide Phenytoin Increased level of pimozide (probably)217 Increased level of phenytoin221.224 Inhibition of P450 1A2 Increased sedation and (strong). fluvoxamine45.48.48.51.127 Inhibition of P450 1A2 and Increased EPS and Theoretical concern 3A4 by fluvoxamine45. Inhibition of multiple P450 Increased arrhythmia risk enzymes and P-glycoprotein and anticholinergic by fluvoxamine34.

228 Hypertensive crisis18. combined with increased serum norepinephrine due to clozapine’s α 2 blockade181. combined with serotonin. combined with norepinephrine and dopamine reuptake inhibition by stimulants One case known to the authors Drug–Drug Interaction Primer Potentially fatal . 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 crisis18.19.227 MAOIs. norepineprine.19 Decreased metabolism of norepinephrine and dopamine by MAOIs. and dopamine reuptake inhibition by other antidepressants Decreased metabolism of Hypertension norepinephrine by MAOIs.286 TABLE A–1.202.

Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Ziprasidone Pharmacokinetic results n/a Mechanisms Clinical consequences Comments Potentially fatal. Combination can increased risk of serotonin increase mirtazsyndrome219 apine levels by as much as fourfold Fluvoxamine Inhibition of P450 1A2.137.146.88. and 3A4 by fluvoxamine34.89 287 . 2D6. 50.48.197.145. 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. 134.198 Possible loss of therapeutic efficacy Somnolence (perhaps).An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.89. but a theoretical concern for this combination Central serotonin Decreased metabolism of serotonin and norepinephrine syndrome and/or hypertensive crisis229 by MAOIs.

198 efficacy Drug–Drug Interaction Primer Inhibition of P450 2D6 by bupropion84.137. 2) likely loss of therapeutic efficacy Theoretical concern . diplopia.161.145. 197.100.89.90 by MAOIs. 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..200. tremor. etc. sedation.288 TABLE A–1.19.134. 2) induction of P450 3A4 by carbamazepine97.135.160. nausea.198 Acute dysphoric anxiety 1) Ataxia.98 1) Inhibition of P450 3A4 by nefazodone46. dysarthria. combined with increased presynaptic release of serotonin and norepinephrine by mirtazapine Induction of P450 3A4 by Possible loss of therapeutic phenytoin88.

97.161. 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 .98 Central serotonin Decreased metabolism of serotonin and norepinephrine syndrome and/or hypertensive by MAOIs. combined with serotonin and norepinephrine crisis18.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.198 Inhibition of 1) P450 3A4 by nefazodone46.97.98.67.233 and 2) mCPP Inhibition of P450 2D6 by Acute dysphoric anxiety fluoxetine plus norfluoxetine34. 95 reuptake inhibition by nefazodone Inhibition of P450 2D6 by Acute dysphoric anxiety paroxetine34.40.100.98 Induction of P450 3A4 by phenytoin97. 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. 19.117 and 2) P450 2D6 by pimozide97.117 Potentially fatal Theoretical concern Likely loss of therapeutic Theoretical concern.

sedation.53 Comments Theoretical concern MAOIs Potentially fatal Drug–Drug Interaction Primer Nefazodone Phenothiazine antipsychotics Increased levels of mCPP Increased levels of phenothiazine antipsychotics55.290 TABLE A–1.19.104.97.67.52.67. increased sweating Central serotonin syndrome18.112 by paroxetine Clinical consequences Increased risk of seizures Dry mouth. 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 paroxetine42.54.194 Acute dysphoric anxiety Increased EPS and other side effects Theoretical concern Combining with mesoridazine or thioridazine can increase arrhythmogenic potential . combined with serotonin reuptake inhibition by paroxetine Inhibition of P450 2D6 by paroxetine34.98 Inhibition of P450 2D634. constipation.83 Inhibition of P450 2D6 by paroxetine34.103. fatigue.107 and P-glycoprotein47.86 Decreased metabolism of serotonin by MAOIs.

70.147.208 Clinical consequences EPS.75.65.198 Increased risk of seizures Possible loss of therapeutic efficacy Theoretical concern 291 . 145.112.57.235.36.130 Inhibition of P450 2D6 and P-glycoprotein by paroxetine21.137.148.195.67.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.56.47.134.75. 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. 69.83 Induction of P450 2B6. and 3A4 by carbamazepine43.47. increased prolactin Comments Average increase in the “risperidone active moiety” of roughly 45% TCAs Increased levels of TCAs54.197.67.236 Increased arrhythmia risk and anticholinergic symptoms Sertraline Bupropion Carbamazepine Increased level of bupropion85 Decreased level of sertraline237 Inhibition of P450 2B6 by sertraline42.64. 2C9.34.

227.161. increased risk glucuronosyltransferase of emergence of rash (UGT) 1A4 by sertraline22.159.19. and 3A4 by phenytoin56.23.57.150.238 Possible loss of therapeutic efficacy .198 Central serotonin syndrome18. combined with serotonin reuptake inhibition by sertraline Induction of P450 2B6. 5′-diphosphate confusion.62 Drug–Drug Interaction Primer MAOIs n/a Phenytoin Decreased level of sertraline237 Decreased metabolism of serotonin by MAOIs.151 Potentially fatal Sertraline (continued) Lamotrigine Increased level of lamotrigine62 Inhibition of uridine Increased somnolence. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments Lamotrigine levels typically double with this combination. Risk of rash and risk of progression to Stevens-Johnson syndrome or toxic epidermal necrolysis exist with this combination.292 TABLE A–1.147. 2C9/19.

possible increased level of pimozide233 Increased levels of TCAs58.195 Increased arrhythmia risk and anticholinergic symptoms TCAs Bupropion Increased levels of TCAs84.240 Mechanisms Clinical consequences Comments TCAs Unclear.69.59–61. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pimozide Pharmacokinetic results Unclear.34.64.208 by sertraline Inhibition of P450 2D6 by bupropion21.75–77.65.195 and P-glycoprotein36.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.85 293 .58–61.70.41.44.239 Increased arrhythmia risk Inhibition of multiple P450 and anticholinergic enzymes (mostly 2D6 and symptoms 2C19)21.75.236.64.47. possible inhibition Increased EPS and of P450 3A4 and 1A2 by arrhythmogenic potential sertraline41.84.

34.31.195 while clomipramine is reportedly increased. is 2) inhibition of P450 2C19 reliably decreased by by carbamazepine75.64. which carbamazepine43.74–76. which is reportedly increased142 Citalopram.198. Possible loss of therapeutic It is confusing that and 3A4 and UGT1A4 by efficacy amitriptyline. P450 2C19 for its metabolism.195 symptoms Drug–Drug Interaction Primer .149.134.137.146.78. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments TCAs (continued) Carbamazepine 1) Decreased levels of TCAs195.241. Carbamazepine’s activity at P450 2C8/ 9 and 2C19 is not yet completely understood. 2C9. Inhibition of P450 2D6 by Increased arrhythmia risk citalopram and by and anticholinergic escitalopram21. 2) except for level of clomipramine.197.294 TABLE A–1.141 carbamazepine.38 1) Induction of P450 1A2.148. escitalopram Increased levels of secondary-amine TCAs35. also relies strongly on 145.

52. 63.75–77.65.208 by fluoxetine plus norfluoxetine Inhibition of both multiple Increased arrhythmia risk P450 enzymes and and anticholinergic P-glycoprotein by symptoms fluvoxamine34.195.52.69.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.86.48.36.223.46.40.195 and P-glycoprotein36. 60.224 Inhibition of both multiple P450 enzymes21. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Duloxetine Pharmacokinetic results Increased levels of TCAs87 Increased levels of TCAs20.69.75.41.70.75.43.36.206.44.47.70.208 Haloperidol Increased levels of TCAs Inhibition of P450 2D6 and Increased arrhythmia risk P-glycoprotein by haloperidol and anticholinergic and reduced haloperidol symptoms metabolites21.195 Clinical consequences Increased arrhythmia risk and anticholinergic symptoms Increased arrhythmia risk and anticholinergic symptoms Comments Fluoxetine Fluvoxamine Increased levels of tertiary-amine TCAs75.73–77.50.65.64.45.111.47.64.208 Theoretical concern 295 . 115.64.34.116.207 Mechanisms Inhibition of P450 2D6 by duloxetine21.

296 TABLE A–1. combined with serotonin and norepinephrine reuptake inhibition by TCAs Inhibition of P450 2D6 and Increased arrhythmia risk P-glycoprotein by and anticholinergic paroxetine21.235.195.36.70.110. 64.70.19.36.236 Central serotonin Decreased metabolism of Potentially fatal serotonin and norepinephrine syndrome and/or hypertensive crisis18. 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 TCAs54.64.113. symptoms 75.75.69.110.69.242 Inhibition of P450 2D6 and P-glycoprotein by phenothiazine antipsychotics21.195.208 (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 .47.34.67.195.52.183 by MAOIs.111.208 Drug–Drug Interaction Primer Phenothiazine antipsychotics Increased levels of TCAs73.206.65.

75–77.21.74–76.64. 80.36.78.An Overview of Psychotropic Drug–Drug Interactions TABLE A–1.236.117.149.58–61.243 Clinical consequences Comments Possible loss of therapeutic Theoretical.47.70.208 in addition to synergistic QT prolongation233 Inhibition of both multiple P450 enzymes (mostly 2D6 and 2C19)21.44.69.198 Inhibition of P450 2D6.64.195 and P-glycoprotein 36.70.240 Increased arrhythmia risk and anticholinergic symptoms Ziprasidone n/a Increased arrhythmogenic potential 297 . but likely efficacy Increased arrhythmogenic Theoretical concern potential Pimozide Sertraline Increased levels of TCAs58. and P-glycoprotein by pimozide. 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 phenytoin74–76.34.208 by sertraline Synergistic QT prolongation26. 3A4.41.195.69.159–161.

norepinephrine. Risperidone active moiety is the sum of risperidone and 9-hydroxy-risperidone. and sometimes dopamine by MAOIs. combined with serotonin.189 Note.19. and dopamine reuptake inhibition by venlafaxine Clinical consequences Comments Central serotonin Potentially fatal syndrome and/or hypertensive crisis18.298 TABLE A–1. norepinephrine. TCAs=tricyclic antidepressants. Significant drug–drug interactions involving antidepressants (continued) Antidepressant and interacting drug Venlafaxine MAOIs Pharmacokinetic results n/a Mechanisms Decreased metabolism of serotonin. MAOIs=monoamine oxidase inhibitors. Drug–Drug Interaction Primer .

efficacy 145.134.197.An Overview of Psychotropic Drug–Drug Interactions TABLE A–2.160.137.161.198 Phenytoin Clozapine Aripiprazole Induction of P450 3A4 by Possible loss of therapeutic Theoretical concern efficacy phenytoin118. 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 antipsychotic118.120–122 299 .120–122 Carbamazepine Induction of P450 3A4 by Possible loss of therapeutic carbamazepine118.198 Aripiprazole binds more Possible clinical avidly to the D2 decompensation during receptor than any other antipsychotic crossover titrations antipsychotic118.

46.244.197.60. 2C9/19.51. Clozapine levels anticholinergic symptoms.137.to fourfold 3A4.145.300 TABLE A–2.41.123.44. well as P-glycoprotein (weak contribution)47. roughly 50% with this combination Drug–Drug Interaction Primer .40. increase three. 2C9.112 (weak contribution to clozapine bioavailability) by fluoxetine plus norfluoxetine Clozapine levels can Inhibition of P450 1A2.146. typically increase by seizure risk. 2D6 (weak) and anticholinergic symptoms. Increased sedation. 3A4. 149. and UGT1A4 by carbamazepine43.123. Significant drug–drug interactions involving antipsychotics (continued) Antipsychotic and interacting drugs Pharmacokinetic results Mechanisms Induction of P450 1A2. 2C9/19.48.45.50. 2D6.52. etc.198 Clinical consequences Comments Clozapine (continued) Carbamazepine Decreased level of clozapine214. 112 by fluvoxamine Possible loss of therapeutic Synergistic risk of blood efficacy dyscrasias (agranulocytosis from clozapine and aplastic anemia from carbamazepine)246 Increased sedation.34.245 Fluoxetine Increased level of clozapine201 Fluvoxamine Increased level of clozapine213–216 Inhibition of P450 1A2.134.148. and 3A4. etc.43.50. 123–125. 124 as well as P-glycoprotein47.124 as seizure risk.34.

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.An Overview of Psychotropic Drug–Drug Interactions TABLE A–2.123–125. 3A4 and UGT1A4 efficacy by phenytoin50.159–161. 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. combined with increased serum norepinephrine due to clozapine’s α2 blockade Induction of P450 2C9/ Possible loss of therapeutic 19. 149. 120–122 301 .

52.64.36. 145. 70.52. Significant drug–drug interactions involving antipsychotics (continued) Antipsychotic and interacting drugs Pharmacokinetic results Mechanisms Clinical consequences Comments Haloperidol (continued) Carbamazepine Decreased level of haloperidol244.198 Inhibition of P450 2D6 Increased arrhythmia risk Theoretical concern and P-glycoprotein and anticholinergic symptoms by haloperidol and reduced haloperidol metabolites21.50.249 Induction of P450 1A2 Possible loss of therapeutic and 3A4 (and possibly efficacy pertinent phase II enzymes) by carbamazepine114. Increased EPS and other 3A4. 250 Inhibition of P450 1A2.146.160–162.47.248.115.134.116.137.111.195.149.198 Fluvoxamine Increased level of haloperidol210.69.114.48.115 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. and side effects P-glycoprotein by fluvoxamine45.302 TABLE A–2.208 .197. 112.

phenytoin22.23. of EPS and P-glycoprotein by fluvoxamine34.149 Possible loss of therapeutic efficacy Fluvoxamine Increased level of olanzapine127.220 Inhibition of P450 1A2 Increased sedation and risk (strong).47.149 efficacy but likely 303 . 146. 127 Phenytoin Decreased level of olanzapine Induction of UGT1A4 by Possible loss of therapeutic Theoretical concern.253 Clinical consequences Comments Aripiprazole binds more Possible clinical avidly to the D2 decompensation during receptor than any other antipsychotic crossover titrations antipsychotic118.An Overview of Psychotropic Drug–Drug Interactions TABLE A–2. 2D6 (weak).48.23.120–122 Carbamazepine Induction of P450 1A2 and UGT1A4 by carbamazepine22.127. 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 olanzapine252.52.112.

38 Increased EPS and One known case of arrhythmogenic potential serious bradycardia205 Increased EPS and Theoretical concern arrhythmogenic potential .60 Inhibition of P450 1A2 and 3A4 by fluvoxamine45. 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)41.304 TABLE A–2.198 Drug–Drug Interaction Primer Citalopram.137.197. 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 antipsychotic118.48. 145.134.46.120–122 Carbamazepine Induction of P450 1A2 Possible loss of therapeutic Theoretical concern and 3A4 by efficacy carbamazepine117.117 Increase in the QT interval Theoretical concern without an increase in the level of pimozide35.146.50.

21.160.239 Increased levels of TCAs Inhibition of P450 2D6.233 and 2) metachlorophenylpiperazine Decreased level of pimozide Unclear.70.117 Induction of P450 3A4 by phenytoin117. possible inhibition of P450 3A4 and 1A2 by sertraline41. 2) P450 2D6 by pimozide97.69.208 in addition to synergistic QT prolongation233 n/a Synergistic QT prolongation26 Clinical consequences Comments Phenytoin Sertraline 1) Potentially fatal. 1) Increased risk of QT 2) theoretical concern prolongation leading to a malignant arrhythmia.117.80.100.195. possible increased level of pimozide233 Inhibition of 1) P450 3A4 by nefazodone46. 74–76. Significant drug–drug interactions involving antipsychotics (continued) Antipsychotic and interacting drugs Nefazodone Pharmacokinetic results Mechanisms Increased levels of 1) pimozide186.98.198 Unclear.36.An Overview of Psychotropic Drug–Drug Interactions TABLE A–2.59–61. 3A4 and P-glycoprotein by pimozide.161.64.117. 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 .

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

134. efficacy 145. 2C9.137.33. and UGT1A4 by efficacy carbamazepine43.145.145. Possible loss of therapeutic 3A4.197.244. escitalopram Clozapine Decreased level of bupropion192. 134.137.198 Duloxetine Decreased level of duloxetine Induction of P450 1A2 by carbamazepine37.245 Mechanisms Clinical consequences Comments Induction of P450 3A4 by Possible loss of therapeutic carbamazepine118.146.50.193 Decreased levels of citalopram and escitalopram196 Decreased level of clozapine214.197.134.146 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 . Significant drug–drug interactions involving mood stabilizers Mood stabilizer and interacting Pharmacokinetic drug results Carbamazepine Aripiprazole Decreased level of aripiprazole118 Bupropion Citalopram.148.37.147 efficacy Induction of P450 3A4 by Possible loss of therapeutic carbamazepine32. efficacy 197.123–125.198 Induction of P450 1A2.314 TABLE A–3.198 Induction of P450 2B6 by Possible loss of therapeutic carbamazepine83.137.149.

135.198 Clinical consequences Ataxia.60. 2) induction of P450 1A2 by carbamazepine48. The decrease in dysarthria. 2C9)42. tremor. 1A2.43.200 and P-glycoprotein 47. theoretical concern Haloperidol.212 and 2) decreased level of fluvoxamine Ataxia.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3. diplopia. dysarthria. Comments Fluvoxamine 1) Increased level of carbamazepine211.149. 114.146.200 and P-glycoprotein47. 2B6. nausea. tremor. etc. fluvoxamine levels is a etc.51.138 by fluvoxamine.135. 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. mirtazapine Decreased level of haloperidol or mirtazapine230.244. 2B6.48.52.137.145.45.146 Induction of P450 1A2 and 3A4 by carbamazepine88.46. nausea. 1A2.248.50.89. 2C9)41–43.249 Possible loss of therapeutic efficacy 315 . sedation. diplopia. sedation.138 by fluoxetine plus norfluoxetine 1) Inhibition of multiple P450 enzymes (3A4.197.134.

dysarthria.149 and carbamazepine22. 2) likely loss of therapeutic efficacy .316 TABLE A–3.11-epoxide with this combination is controversial.244.23. mirtazapine 1) Increased level of 1) Inhibition of P450 3A4 carbamazepine and by nefazodone46. Drug–Drug Interaction Primer Mirtazapine Nefazodone Decreased level of See information for haloperidol or interaction of mirtazapine230.11-epoxide260 confusion.198 Possible loss of therapeutic efficacy 1) Ataxia. diplopia.200. sedation. and others suggested no such increase260–263 Carbamazepine (continued) Lamotrigine 1) Decreased level of 1) Induction of UGT1A4 by 1) Possible loss of lamotrigine137. tremor.197. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Mechanisms Clinical consequences Comments The increase in carbamazepine10. therapeutic efficacy.149. dysarthria.134. level of carbamazepinenausea.137.100. 2) possible increase in 2) mechanism unknown 2) possible ataxia.249 carbamazepine with haloperidol. nausea. one study suggested this increase occurs. sedation. etc.248. etc. 145. tremor.. diplopia.135. 10. 2) decreased level of 2) induction of P450 3A4 nefazodone232 by carbamazepine97.

159–161.147. sedation. 198.156 Although evidence supports the increase in phenytoin levels in this combination.253 1) Decreased level of carbamazepine137. nausea.23. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Olanzapine Decreased level of olanzapine252. phenytoin135. carbamazepine and phenytoin package inserts mention possible decreases due to induction. 1) Possible loss of 2C9. P450 2C19 by carbamazepine68. and 3A4 by therapeutic efficacy. tremor. 2) possible nystagmus.127.143 Mechanisms Clinical consequences Comments Phenytoin Induction of P450 1A2 and Possible loss of therapeutic UGT1A4 by efficacy carbamazepine22. It is unclear how carbamazepine’s 2C19 inhibition could overcome its 2C9 induction to produce elevated phenytoin levels.149 1) Induction of P450 2B6. 317 . dysarthria.141.200 . etc.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3.146. 2) inhibition of ataxia.143 and 2) reported increased level of phenytoin141.

197.134.198 Drug–Drug Interaction Primer Sertraline Induction of P450 2B6.137. Possible loss of therapeutic and 3A4 by efficacy carbamazepine43.197. confusion.129. hydrolase) Induction of P450 3A4 by Possible loss of therapeutic carbamazepine130.57.134. 2C9.56.137.145. inhibition of epoxide etc. 145.145. 134.147. unknown (possibly dysarthria.11epoxide255 Decreased level of risperidone257–259 Decreased level of sertraline237 Mechanisms Induction of P450 1A2 and 3A4 by carbamazepine117. diplopia. 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 quetiapine129.146. sedation.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. 2) mechanism 2) possible ataxia. 254 and 2) increased level of carbamazepine-10. nausea.148. tremor.137. 145.134.198 .318 TABLE A–3. carbamazepine128.137. efficacy 197.197.198 .

137.241 2) except 2C9.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3. Carbamazepine’s activity at P450 2C8/9 and 2C19 is not yet completely understood.141 Topiramate 1) Decreased level of 1) Induction of phase II topiramate163. clomipramine.145.148.164. 2) inhibition of P450 2C19 by carbamazepine75.264 and metabolism by carbamaze2) possible decreased pine (possibly at UGT level of carbamazepine 1A4)149.78. for the level of 74–76.149. Result #2 is a theoretical concern Tricyclic 1) Decreased levels of 1) Induction of P450 1A2.195.265. 2) induction (mild) of P450 3A4 by topiramate135. Possible loss of therapeutic antidepressants TCAs.167. and 3A4 and UGT1A4 efficacy (TCAs) by carbamazepine37.197. should be reliably decreased by carbamazepine195 and that the level of clomipramine is reportedly increased. which is reportedly increased142 198. 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. which relies strongly on P450 2C19 for its metabolism.200 Possible loss of therapeutic efficacy 319 .163.146.43.134.168.

175.103.79.149. diplopia.107.134. confusion. 108. 198.11valproate137. metabolite. tremor.43.145. 2) transaminase elevations or even frank 2) increased production carbamazepine.114.146. nausea.197. 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 1A2.137.117.172. 148.134. of the hepatotoxic 2) induction of P450 2C9 4-ene-valproate (likely) by carbamazepine.320 TABLE A–3.174.145. 3A4.171 hepatitis.198 Drug–Drug Interaction Primer . sedation.266 metabolism by efficacy.170 3) inhibition of dysarthria.268 epoxide137 Decreased level of Induction of P450 3A4 by Possible loss of therapeutic ziprasidone134 carbamazepine26.149. Possible loss of therapeutic and UGT1A4 by efficacy carbamazepine23.210 Valproate Ziprasidone 1) Decreased level of 1) Induction of phase II 1) Possible loss of therapeutic valproate.172.137.267 and etc. 3) possible ataxia. efficacy 197. 3) increased level of epoxide hydrolase by carbamazepine-10.

2) possible increase in 2) mechanism unknown nausea. diplopia.11-epoxide260 etc.150.269 efficacy lamotrigine149. 10. occurs.149 and efficacy.62 confusion. Lamotrigine level can Sertraline Increased level of sertraline22. one study suggested it 10. and increased double. controversial. sedation. and others suggested no such increase260–263 Oxcarbazepine Decreased level of Induction of UGT1A4 by Possible loss of therapeutic lamotrigine154 oxcarbazepine22. Risk of rash lamotrigine62 risk of emergence of rash and progression to Stevens-Johnson syndrome or toxic epidermal necrolysis exist with this combination.23. 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 lamotrigine137.151 321 .11-epoxide is level of carbamazepinedysarthria.154 efficacy Induction of UGT1A4 by Possible loss of therapeutic Phenytoin Decreased level of phenytoin149.269 Inhibition of UGT1A4 by Increased somnolence. confusion.149. 2) possible ataxia.23. carbamazepinecarbamazepine22. tremor.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3.23.

dysarthria. 154 1) Inhibition of P450 2C19 by oxcarbazepine141.268. and increased risk of emergence of rash. 2) possible loss of therapeutic efficacy Comments 1) Lamotrigine level typically doubles with this combination.154. Risk of rash and risk of progression to Stevens-Johnson syndrome or toxic epidermal necrolysis exist with this combination150.322 TABLE A–3.270 Induction of UGT1A4 by oxcarbazepine22.171 Clinical consequences 1) Increased somnolence.269. confusion. sedation. 2) possible loss of therapeutic efficacy . 2) theoretical concern Drug–Drug Interaction Primer Oxcarbazepine Lamotrigine Decreased level of lamotrigine154 Phenytoin 1) Increased level of phenytoin141 and 2) decreased level of oxcarbazepine269.151. tremor. ataxia.154.162 Possible loss of therapeutic efficacy 1) Nystagmus. nausea. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Lamotrigine (continued) Valproate 1) Increased level of lamotrigine149. 2) likely mild phase II induction by lamotrigine151.269 and 2) mild (about 25%) decrease in valproate levels151 Mechanisms 1) Inhibition of UGT1A4 by valproate149.. etc. 2) induction of phase II metabolism by phenytoin149. 23.

carbamazepine package by carbamazepine68. nausea. Induction of P450 2B6 by efficacy but likely phenytoin83.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3.147.156 insert notes possible decreases in phenytoin levels due to induction.147 1) Induction of P450 2B6.Possible loss of therapeutic olism by oxcarbazepine154 efficacy Induction of P450 3A4 by Possible loss of therapeutic Theoretical concern phenytoin118. and 3A4 by efficacy.141.159161. yet the 2) inhibition of P450 2C19 sedation. ataxia.143 323 . tremor. etc. toin levels with this combination.200. It is unclear how carbamazepine’s 2C19 inhibition could overcome its 2C9 induction to produce elevated phenytoin levels.143 and 2) reported increased level of phenytoin141.198. dysarthria. nystagmus.198 efficacy Possible loss of therapeutic Theoretical concern. 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. 1) Possible loss of therapeutic Some evidence supports 2C9.160. Decreased level of aripiprazole Bupropion Decreased level of bupropion Carbamazepine 1) Decreased level of carbamazepine137. 2) possible the increase in phenyphenytoin135.161.

sedation.155. fluvoxamine Nystagmus. tremor. 221. 159–161.221. nausea. fluvoxamine Increased level of phenytoin204.68. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Phenytoin (continued) Citalopram. etc.123–125. nausea.198 Fluoxetine.158 by fluoxetine plus norfluoxetine and by fluvoxamine45. dysarthria. sedation. 222 Inhibition of both P450 2C9/1943. 159–161. Decreased levels of escitalopram citalopram and escitalopram Clozapine Decreased level of clozapine247 Mechanisms Induction of P450 3A4 and 2C19 by phenytoin32.222 Fluvoxamine Increased level of phenytoin204. tremor. etc.33. ataxia. ataxia.156 and P-glycoprotein47.52 See information for interaction of phenytoin with fluoxetine.324 TABLE A–3. and UGT1A4 by phenytoin50. dysarthria. .149. Drug–Drug Interaction Primer Nystagmus.51. 3A4.44.198 Clinical consequences Possible loss of therapeutic efficacy Possible loss of therapeutic efficacy Comments Theoretical concern Induction of P450 2C9/19.48.

nausea.23. 2) possible loss of therapeutic efficacy 325 .141.89.270 Mechanisms Induction of P450 3A4 (and possibly pertinent phase II enzymes) by phenytoin88. 2) induction of phase II metabolism by phenytoin149.161. efficacy but likely Possible loss of therapeutic Theoretical concern.269 See information for interaction of phenytoin with haloperidol.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.198 Induction of UGT1A4 by phenytoin22..251 Decreased level of nefazodone Decreased level of olanzapine 1) Increased level of phenytoin141 and 2) decreased level of oxcarbazepine269. efficacy but likely 1) Nystagmus.160–162.149 1) Inhibition of P450 2C19 by oxcarbazepine68.149. etc. Significant drug–drug interactions involving mood stabilizers (continued) Mood stabilizer and interacting Pharmacokinetic drug results Haloperidol.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3. ataxia. sedation. tremor. mirtazapine Decreased level of haloperidol or mirtazapine231.269 Decreased level of haloperidol or mirtazapine231.156.198 Induction of UGT1A4 by phenytoin149.251 Decreased level of lamotrigine149. dysarthria. mirtazapine Induction of P450 3A4 by phenytoin97.

161.129.198 Theoretical concern.198 Induction of P450 3A4 by phenytoin128. 159–161.160.161.57.198 efficacy Induction of P450 2B6. 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 phenytoin117.149.159.161. and 3A4 by efficacy phenytoin56. but likely .326 TABLE A–3.160.78.198 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 phenytoin130.161.160.198 Induction of P450 2C19 and Possible loss of therapeutic efficacy 3A4 and UGT1A4 by phenytoin74–76. Possible loss of therapeutic 2C9/19.147.

the patient’s free of phenytoin. disproportionate from plasma protein binding tremor.. 2) induction of P450 2C9/19 or even frank hepatitis and phase II metabolism by 2) decreased level of generally not phenytoin149..272 by of therapeutic efficacy.160. checked.170.273.167.171. dysarthria.155. etc. tremor.170 combined with 4-ene-valproate phenytoin metabolite172.149. With this combination.109. with a combined with displacement sedation. level) should be fraction of 3) transaminase elevations valproate148. valproate172. 2) induction of phase II metabolism by phenytoin149.162.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3. nausea.268. etc.272.106.267 327 .264.162–164 Induction of P450 3A4 and UGT1A4 by phenytoin79.271 Mechanisms 1) Inhibition of P450 2C19 by topiramate68. ataxia.156. sedation.273 It is phenytoin175.159.166.173 1) Nystagmus. 265. ataxia. 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. dysarthria. 161. 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. nausea.198 Clinical consequences 1) Nystagmus. 2) possible loss phenytoin level (as opposed to a total increase in the free sites. and necessary to check a free valproate level 3) increased production 3) induction of P450 2C9 when valproate is of the hepatotoxic (likely) by phenytoin159.156.

dysarthria.162–164 Drug–Drug Interaction Primer . ataxia. 2) possible loss 2) decreased level of 2) induction of phase II of therapeutic efficacy topiramate163.200 Oxcarbazepine Decreased level of Induction of phase II Possible loss of therapeutic topiramate265 metabolism by efficacy oxcarbazepine154 1) Inhibition of P450 2C19 1) Nystagmus.167.328 TABLE A–3.264 and efficacy theoretical concern metabolism by 2) possible decreased carbamazepine (possibly at level of carbamazepine UGT1A4)149.166. Phenytoin 1) Increased level of by topiramate68.167.168..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. 2) induction (mild) of P450 3A4 by topiramate135. metabolism by 265.163. phenytoin271 and tremor. etc.134.160.264.161.164.268. nausea.271 phenytoin149. 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 phenytoin26.156. sedation.

diplopia. etc. metabolism by efficacy.171. 3) possible ataxia.171 Stevens-Johnson syndrome or toxic epidermal necrolysis exist with this combination150.An Overview of Psychotropic Drug–Drug Interactions TABLE A–3.151. 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. hepatitis.175. combination. sedation. 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 valproate172.268.170. metabolite172. and carbamazepine43. 154. 269 valproate149. 2) transaminase elevations or even frank 2) increased production carbamazepine149.148. confusion. 4-ene-valproate (likely) by dysarthria. tremor.11hydrolase by valproate137.154. of the hepatotoxic 2) induction of P450 2C9 nausea. 2) theoretical concern 329 . and increased typically doubles in risk of emergence of rash. 1) Lamotrigine level lamotrigine. 3) increased level of 3) inhibition of epoxide carbamazepine-10.267. confusion.268 epoxide137 Lamotrigine 1) Increased level of 1) Inhibition of UGT1A4 by 1) Increased somnolence.174.269.149.266.

170 combined with 4-ene-valproate phenytoin metabolite172. 2) possible loss phenytoin level (as opposed to a total increase in the free sites. and necessary to check a free valproate level 3) increased production 3) induction of P450 2C9 when valproate is of the hepatotoxic (likely) by phenytoin159.162.272.273. With this combination.170.273 It is phenytoin175.330 TABLE A–3. the patient’s free of phenytoin.. UGT= uridine 5′-diphosphate glucuronosyltransferase. ataxia.155. checked. Drug–Drug Interaction Primer . 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. disproportionate from plasma protein binding tremor.159.267 Note. etc.173 1) Nystagmus.171.156. dysarthria.272 by of therapeutic efficacy. with a combined with displacement sedation. level) should be fraction of 3) transaminase elevations valproate148. 2) induction of P450 2C9/19 or even frank hepatitis and phase II metabolism by 2) decreased level of generally not phenytoin149. nausea. valproate172.

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 carbamazepine134.278–280 Increased somnolence Increased somnolence Increased somnolence Possible loss of therapeutic efficacy Possible loss of therapeutic efficacy Theoretical concern 331 .279 Inhibition of P450 3A4 by clarithromycin and by erythromycin 186.50.274 Induction of P450 3A4 by phenytoin 160.274–276 Inhibition of P450 3A4 by fluoxetine and by fluvoxamine45. fluvoxamine Nefazodone Phenytoin St.161.An Overview of Psychotropic Drug–Drug Interactions TABLE A–4.274 Clarithromycin. John’s wort274.274 Inhibition of P450 3A4 by nefazodone46.145.100 Decreased level of alprazolam Decreased level of alprazolam278.137.186.100.46.274 Induction of P450 3A4 by St. efficacy alprazolam145 197.277 Increased level of alprazolam96. erythromycin Fluoxetine. John’s wort Increased level of alprazolam274 Increased level of alprazolam217.

282 Inhibition of P450 3A4 Increased somnolence. nausea. erythromycin Grapefruit juice Increased level of buspirone275.30. erythromycin 186.137.282 Theoretical concern283 Inhibition of P450 3A4 by Increased somnolence. (in the gut) by grapefruit headache. 284 Increased level of buspirone285 Drug–Drug Interaction Primer Induction of P450 3A4 by Possible loss of therapeutic carbamazepine134. etc. juice186.275. β-oxidation by aspirin29.332 TABLE A–4.275.182 Buspirone (metabolized by P450 3A4) Carbamazepine Decreased level of buspirone282 Clarithromycin. nausea. confusion.282.172. 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 valproate29.285. etc. displacement of valproate incoordination. efficacy 197.281 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.275.30. nausea. and inhibition of vomiting.276.145.286 . etc. clarithromycin and by headache.

282 Induction of P450 3A4 by phenytoin 160. etc. 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 nefazodone46.186.19. and/or its discontinuation.123. central serotonin syndrome has been reported with this combination278 Although this combination typically raises clozapine levels only about 25%. headache.289. can be important for individual patients Caffeine (metabolized by P450 1A2) Clozapine Increased level of clozapine287–289 Inhibition of P450 1A2 by caffeine50.282 Increased somnolence.An Overview of Psychotropic Drug–Drug Interactions TABLE A–4.282 Induction of P450 3A4 by St. John’s wort275. Possible loss of therapeutic efficacy Possible loss of therapeutic efficacy Comments Monoamine oxidase n/a inhibitors (MAOIs) Nefazodone Phenytoin St.275. etc.290 Sedation. 333 . hypersalivation. this effect.161.275. John’s wort Increased level of buspirone282 Decreased level of buspirone282 Decreased level of buspirone Theoretical concern283 Theoretical concern. nausea.278–280 Clinical consequences Central serotonin syndrome and/or hypertensive crisis18. constipation.100. blurry vision.

290 tachycardia. Fluvoxamine Increased level of fluvoxamine48.137. etc.297 Induction of UGT1A4 by Possible loss of therapeutic ethinylestradiol22. etc. 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.296. 294. ethinylestradiol197.297 efficacy This combination typically produces a 50% decrease in lamotrigine levels Oxcarbazepine Decreased level of ethinylestradiol153. breakthrough bleeding. anxiety.145. excessive caffeine48 diuresis.298.23. 289.334 TABLE A–4.295 breakthrough bleeding. Increased renal excretion Possible loss of therapeutic Lithium Decreased level of of lithium caused by efficacy lithium291. .295 Drug–Drug Interaction Primer Lamotrigine Decreased level of lamotrigine296.292 caffeine293 Ethinylestradiol (metabolized by P450 3A4) Induction of P450 3A4 by Unintended pregnancy. etc. 294 197. Carbamazepine Decreased level of carbamazepine134.299 Induction of P450 3A4 by Unintended pregnancy. oxcarbazepine153.

285. John’s wort Decreased level of ethinylestradiol278.138.302–304 335 .161. (in the gut) > 1A2 and dysarthria.286 Inhibition of P450 3A4 Ataxia. 286. 294. nausea. 280. etc.295 breakthrough bleeding.299 Grapefruit juice Buspirone Increased level of buspirone285 Increased level of carbamazepine301 Carbamazepine Inhibition of P450 3A4 (in Increased somnolence. etc. grapefruit juice135.275.295 breakthrough bleeding. etc. juice186.295 breakthrough bleeding. phenytoin 160.300 Topiramate Decreased level of ethinylestradiol169. P-glycoprotein by tremor.An Overview of Psychotropic Drug–Drug Interactions TABLE A–4. diplopia. etc. topiramate168. Induction of P450 3A4 by Unintended pregnancy. nausea. sedation. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug Phenytoin Pharmacokinetic results Decreased level of ethinylestradiol197.285. St. 294 Mechanisms Clinical consequences Comments Induction of P450 3A4 by Unintended pregnancy. the gut) by grapefruit headache. St. Induction of P450 3A4 by Unintended pregnancy. etc. John’s wort278–280.

137.285.305.) See information for Increased risk of rhabdomyolysis and interaction of HMGCoA reductase inhibitors associated symptoms (fatigue. 307–309 Inhibition of P450 3A4 Increased risk of (in the gut) by grapefruit rhabdomyolysis and juice or nefazodone46.306 Drug–Drug Interaction Primer Grapefruit juice.286. lovastatin. nefazodone Increased ‘‘statin’’ blood level286.306 (fatigue. associated symptoms 186.305. efficacy blood level144 197.) with grapefruit juice. 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. arrhythmogenic potential 304 Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (‘‘statins’’).336 TABLE A–4. myalgias. etc. nefazodone . and simvastatin (metabolized by P450 3A4) Induction of P450 3A4 by Possible loss of therapeutic Carbamazepine Decreased ‘‘statin’’ carbamazepine134. etc.286.100.233 Grapefruit juice (continued) Pimozide Increased level of pimozide Inhibition of P450 3A4 Increased extrapyramidal (in the gut) > 1A2 by symptoms and grapefruit juice285.305.145. 307–309 Nefazodone Increased ‘‘statin’’ blood level286.303. specifically atorvastatin.305. myalgias.

etc.An Overview of Psychotropic Drug–Drug Interactions TABLE A–4. blurry vision. efficacy John’s wort278–280. and angiotensin II angiotensin II receptor receptor antagonists antagonists Loop diuretics Variable or no change Unclear Unclear in lithium levels27 This effect is unpredictable.310 Mechanisms Clinical consequences Comments Induction of P450 3A4 by Possible loss of therapeutic phenytoin 160.305.311–313 of lithium caused by ACE tremor. (ACE) inhibitors inhibitors and confusion. nausea.306 efficacy Induction of P450 3A4 and Possible loss of therapeutic P-glycoprotein by St. converting enzyme level28. vomiting.305. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug Phenytoin St. John’s wort Pharmacokinetic results Decreased ‘‘statin’’ blood level306 Decreased ‘‘statin’’ blood level280. monitoring of lithium level is advised 337 .161.306 Lithium Increased lithium AngiotensinDecreased renal excretion Dizziness.

except amiloride316 Drug–Drug Interaction Primer .28 diuretics. thiazide and potassiumconfusion. blurry vision.338 TABLE A–4. vomiting. 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.292 Thiazide and Increased lithium potassium-sparing level27.315 Decreased renal excretion Dizziness. except amiloride Increased renal excretion Possible loss of therapeutic of lithium caused by efficacy osmotic diuretics and xanthines293.314 drugs (NSAIDs).Increased lithium inflammatory level28. nausea. nausea. sparing diuretics. Osmotic diuretics and xanthines Decreased level of lithium28. from minimal changes to doubling or even greater changes in lithium levels. etc. Close monitoring of lithium level is advised Lithium (continued) Nonsteroidal anti. except aspirin and sulindac Decreased renal excretion Dizziness. etc. vomiting. blurry vision.291. of lithium caused by tremor. of lithium caused by tremor. NSAIDs confusion.

310 339 .306 HMG-CoA reductase inhibitors (‘‘statins’’). St. lovastatin. Induction of P450 3A4 and Possible loss of therapeutic P-glycoprotein by St. central serotonin syndrome has been reported with this combination278 Ethinylestradiol Decreased level of ethinylestradiol278.300 Induction of P450 3A4 by Unintended pregnancy. efficacy John’s wort278–280.279 Decreased level of buspirone Mechanisms Clinical consequences Comments Induction of P450 3A4 by Possible loss of therapeutic St. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug St.278–280 efficacy Induction of P450 3A4 by Possible loss of therapeutic efficacy St.305.An Overview of Psychotropic Drug–Drug Interactions TABLE A–4. 280. John’s wort274.278–280 Theoretical concern. etc. John’s wort275. specifically atorvastatin. John’s wort Alprazolam Buspirone Pharmacokinetic results Decreased level of alprazolam278. John’s wort278–280 breakthrough bleeding. and simvastatin Decreased ‘‘statin’’ blood level280.

John’s wort Synergistic serotonin Increased risk of central All combinations of reuptake inhibition serotonin St.340 TABLE A–4.317 serotonergically active antidepressants are of theoretical concern.317 combined with serotonin reuptake inhibition by St.19.280. John’s wort with syndrome278. serotonin syndrome18. 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. Significant drug–drug interactions involving other psychotropic agents and nonpsychotropic agents (continued) Index drug and interacting drug Pharmacokinetic results Mechanisms Clinical consequences Comments 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 .

322 efficacy fluvoxamine49. levels103.322.49.74– efficacy 76.318.322 efficacy Induction of P450 1A2 by Possible loss of therapeutic Fluvoxamine Decreased level of tobacco smoking48.An Overview of Psychotropic Drug–Drug Interactions 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 Tobacco (smoked) Clozapine Decreased level of Induction of P450 1A2 by Possible loss of therapeutic clozapine318–321 tobacco smoking123.318.322 (TCAs) Induction of P450 1A2 by Possible loss of therapeutic tobacco efficacy smoking103.114. 324–326 including haloperidol Tertiary-amine Decreased level of tricyclic tertiary-amine antidepressants TCAs318.107. tobacco smoking127.321.322 323 Phenothiazines and Decreased typical most other typical antipsychotic antipsychotics.318 Induction of P450 1A2 by Possible loss of therapeutic Olanzapine Decreased level of efficacy olanzapine253.322 341 .322 Induction of P450 1A2 by Possible loss of therapeutic tobacco smoking65.124.

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

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 .344 TABLE B–1.

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

1In vitro evidence exists only for the potential for potent inhibition of 2D6. with higher doses resulting in more potent inhibition than lower doses.346 Drug–Drug Interaction Primer TABLE B–2. 2Sertraline’s inhibition seems to be dose specific. 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. . Names of potent inhibitors are in bold type.

6 Psychotropic drugs. 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%.P450 Tables TABLE B–3. 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 Trazodone2.3 Trimipramine1 Venlafaxine2 347 . Drugs metabolized by 3A4 Antipsychotics Aripiprazole Chlorpromazine2 Clozapine4 Haloperidol5 Perphenazine2 Pimozide6 Quetiapine2 Risperidone7 Ziprasidone2.

7 Terfenadine6.6.10 Chlorpheniramine Ebastine6 Loratadine6.10 Drug–Drug Interaction Primer . 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 Sparfloxacin2.348 TABLE B–3.10 Antiepileptics Carbamazepine Ethosuximide2 Felbamate2 Methsuximide2 Tiagabine2 Valproic acid2 Zonisamide2 Antihistamines Astemizole6.

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.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 .

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

5Also an inhibitor of 2C19. Names of potent inhibitors are in bold type. 4Potent inhibitor of 2C9. 8Also an inhibitor of 2D6.P450 Tables 351 TABLE B–4. 1Also inhibit other P450 enzymes. 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. 2Also a potent inhibitor of 1A2. 7Also a potent inhibitor of 2D6. 1A2. 10Also an inhibitor of 1A2 and 2C9. 6Trade name Kaletra. other Ciprofloxacin2 Norfloxacin3 Quinupristin/ Dalfopristin Sparfloxacin3 Azole antifungals Fluconazole4 Itraconazole Ketoconazole5 Miconazole Note. and 2C9. and 2C19. 9Also a potent inhibitor of 2D6 and 1A2. 3Also an inhibitor of 1A2. . no longer available in the United States. 2C9.

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

to a lesser extent. 1Tertiary tricyclic antidepressants (TCAs) are demethylated by 1A2 and 3A4. 5Demethylated by 1A2 to norclozapine. Clozapine is metabolized to clozapine-N-oxide by 3A4 and. at least 50% of enzymatic metabolism is through 1A2. 2C9. . 10 Weaker pharmacological isomer of racemic warfarin. 8Removed from the United States market. 3Metabolized by other P450 enzymes as well. 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. Names of drugs are in bold type if there is evidence that in normal human use of the drugs. 6Metabolized 30%–40% by 1A2 and some by 2D6. 2N-Demethylation may be preferentially done by 2C19. 4Also metabolized by 3A4. 9Contribution of 1A2 metabolism is small.P450 Tables 353 TABLE B–6. 2D6. and 2C19 also metabolize tertiary TCAs. 71A2 is a minor route of metabolism.2 Clomipramine1 Fluvoxamine3 Imipramine1 Mirtazapine4 Note. glucuronidated by the glucuronosyltransferase (UGT) 1A4. 2D6 and others.

1Flutamide’s primary metabolite is a potent inhibitor of 1A2. 2Scant evidence of 1A2 inhibition. TABLE B–8. 2Induces through stimulation of PAHs. the drugs are potent inhibitors. 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). 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. SSRI = selective serotonin reuptake inhibitor. . 3Weak inhibitor.354 Drug–Drug Interaction Primer TABLE B–7. Names of drugs are in bold type if there is evidence that in normal human use.

NSAID =nonsteroidal anti-inflammatory drug. 1Metabolized by other P450 enzymes as well. 3Also metabolized extensively by phase II enzymes. 5Metabolized by 2C9 to active 17-hydroxyethinylestradiol.P450 Tables TABLE B–9. R-warfarin is metabolized by 1A2. 4The exception to the “statins.” most of which are oxidatively metabolized in part or in full by 3A4. Drugs metabolized by 2C9 Hypoglycemics. 7Metabolized mainly by 3A4 and 1A2. 355 . 2“Glitazones” are metabolized by 2C8 and 3A4. 6S-Warfarin is the more active isomer of warfarin. 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.

However. desmethylamiodarone. an inhibitor of 1A2 and 3A4. is a clinically relevant 2C9 inhibitor. its metabolite. TABLE B–11.356 Drug–Drug Interaction Primer TABLE B–10. Names of potent inhibitors are in bold type. 1Amiodarone. Inducers of 2C9 Phenobarbital Phenytoin Rifabutin Rifampin Rifapentine Ritonavir Secobarbital ?Valproic acid Carbamazepine Cyclophosphamide Ethanol Ifosfamide . is an insignificant 2C9 inhibitor. 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.

8Diazepam is demethylated by 2C19. 1Amitriptyline . 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. and 2C19.P450 Tables 357 TABLE B–12. 5Also metabolized by 3A4. 10Metabolized by 2C19 to the active compound cycloguanil. 62C19 is a minor enzyme in alprazolam’s metabolism. 3A4 is the major enzyme. 7Also metabolized by 2B6 and 3A4. 3A4. 42C19 is a minor enzyme in venlafaxine’s metabolism. 2Also metabolized by 2D6 and 3A4. Diazepam is also metabolized by 3A4. but other P450 enzymes and conjugation enzymes are also involved in clearance. Poor metabolizers at 2C19 have been shown to have higher amitriptyline levels. 3Also metabolized by other P450 enzymes. 92C9 is the major route of metabolism. 2D6 and 3A4 are the major enzymes.

358 Drug–Drug Interaction Primer TABLE B–13. Names of drugs are in bold type if there is evidence of potent inhibition. Carbamazepine ?Norethindrone Phenobarbital Inducers of 2C19 Phenytoin Prednisone Rifabutin Rifampin Ritonavir ?Valproic acid . TABLE B–14. 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.

62E1 is a minor enzyme in verapamil’s metabolism. the hepatotoxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) is created. 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. 3A4 and 2C8 are more important.P450 Tables 359 TABLE B–15. is a minor substrate in normal circumstances. 1Inhibition possibly due to phenyl isothiocyanate. 3Metabolism by 2E1 leads to production of a hepatotoxic metabolite. In cases of overdose or induction of 2E1. . 4Used as a probe for 2E1 activity. Names of drugs are in bold type if there is evidence of clinically potent inhibition. Inhibitors of 2E1 Diethylcarbamate Disulfiram Isoniazid Watercress1 Note. 22E1 12E1 TABLE B–16. 5Metabolized by other hepatic and extrahepatic enzymes.

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

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. 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. Some P-glycoprotein nonsubstrates.

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

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

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

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

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

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

301 with olanzapine. 358. 88–89. 344 drugs metabolized by 3A4. 320 with fluoxetine. 336 with nefazodone. 351 Antineoplastics. 348. 339 Atrial fibrillation. 283 with fluvoxamine. 117–119. 307 with typical antipsychotics. 368 drug–drug interactions with carbamazepine. 355 drug–drug interaction with lithium. 194–195. 192–193. 308 with ziprasidone. 312 Arrhythmias. 352 Antihistamines. 347 Antibiotics. See also individual drug names drug–drug interactions. 23–24. 347 drug–drug interactions with carbamazepine. 362. 201 Antiarrhythmics. 348. 105–106. 104–105. See Atypical antipsychotics drug–drug interactions. 336 with St. 299–313 with carbamazepine. 189–190 . 179–180 Athletics. 357. 28–29. 299 with haloperidol. 277–298 with MAOIs. 283. 31–32. 249–250 Antirejection drugs. 60–61. 348 Antiprogesterone agents. 351. 348 Drug–Drug Interaction Primer Anxiety disorder. 162–163. 355. 351. 155–156. 313 drugs metabolized by 2D6. 348 Antimicrobials. 346 pharmacokinetic features. 162–163. 348 Antiparkinsonian drugs. 227 interaction with valproate. See Lorazepam Atomoxetine. 344 drugs metabolized by 3A4. See Disulfiram Anthrax. 314 with clozapine. 348 Asthma. 348. 337 Aniline. 28–29 Attention-deficit/hyperactivity disorder (ADHD). 323 with pimozide. 332 Astemizole. 56–58. 74–75. 353. 89–91. 172 Atrioventricular heart block. 299 with phenytoin. 224–225 Aspirin. 214–215. See also individual drug names atypical. 147–148 Ativan. 353. 344. 348 Antimalarials. 303 with other antipsychotic agents. 56–57. 180–181 Antabuse. 336 interaction with grapefruit juice. 247–249 withdrawal seizure. 112–113. 359 Anorexia. 158–160. 299. 347 inhibitors of 2D6.378 Angiotensin II receptor antagonists. See also Generalized anxiety disorder Aripiprazole. 211–212. 306 with risperidone. 348 Antipsychotics. 208. 111–112. 61–62 Antiepileptics. 143–144. 354 Antidepressants. 347 inhibitors of 2D6. 285 with phenytoin. 93–94. 346 pharmacokinetic features. 304 with quetiapine. John’s wort. 286 drugs metabolized by 2D6. 285. 351. 299. 344 Atorvastatin. 327 with ziprasidone.

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

319 with topiramate. 238–240. 155–156. 143–144. 99–101. 347. 156–157. 336 with lamotrigine. 205–206. 346. 344. 188–189. 355 Carvedilol. 321 with lovastatin. 192–193. 348. 314 with clozapine. 354. 359 Cardiomyopathy. 6. 144–145. 336 with bupropion. 344. 89. 320 interaction with grapefruit juice. 160–161. 97–99. 281. 365 Chloroquine. 307. 146–147. 102–104. 315 with fluvoxamine. 358. See Green tea Catechol estrogens. 42–43. 320 with valproate. 354 Celecoxib. 250 Carbon tetrachloride. 287 with alprazolam. 349. 314 with escitalopram. 177–178 Carmustine. 344. 368 Cipro. 348. 318 with sertraline. 276. 348. 346. 318 with risperidone. 318 with quetiapine. 210–211. 304. 351. 142–143. 314 with ethinylestradiol. 352 . See Case Studies Index Catechins. 283. 281. 315 with haloperidol. 362 Ciprofloxacin. 287. 346. 368 Chlorpromazine. 354. 328 Drug–Drug Interaction Primer with typical antipsychotics. 368 drug–drug interactions. 357 Cimetidine. 277. 25–26. 288. 351. 283. 299. 277. 44–46. 331 with aripiprazole. 320. 348. 318 with simvastatin. 368 Cisapride. 323 with pimozide. 316. 309. 336 with TCAs. 113–114 Cardiovascular drugs. 332 with citalopram. 334 with fluoxetine. 336 with mirtazapine. 7. 136–137. 168–169. 133. 300. 349 Chloramphenicol. 314 with atorvastatin. 351 Cisplatin. 81–82. See Diltiazem Carisoprodol. 364. 193–194. 352. 294. 315.380 Carbamazepine. 211–212. 316 with olanzapine. 209–210. 182–183. 351. 312. 314 with duloxetine. 356. 344. 316 with nefazodone. 317. 291. 349 Case studies. 131– 133. 348. See Ciprofloxacin Ciprofibrate. 277. 315 with hydroxymethylglutaryl– coenzyme A reductase inhibitors. 346. 368 Chlorzoxazone. 354. 359 Cilostazol. 329 with ziprasidone. 349. 335 pharmacokinetic features. 63–64. 306. 319. See also individual drug names drugs metabolized by 2D6. 32–33. 368 Chlorpheniramine. 302. 191–192. 317 with phenytoin. 365 Cauliflower. 279. 358. 362. See Citalopram Cerivastatin. 362 Cevimeline. 314 with buspirone. 356. 355 Celexa. 303. 22–23. 353. 279. 344 Cardizem. 199–200.

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

46–47. 349. 39–40. 55. See Valsartan Diphenhydramine. 280 with TCAs. 360 Effexor. 362. 69–70. 153–155. 290 with phenothiazine antipsychotics. 352. 44–46. 21–22. 46–47. 368 Drug–drug interactions (DDIs). 181–182 Dilantin. 281 with fluvoxamine. 226–227 Docetaxel. 359 Diflucan. See also individual drug names overview of psychotropic interactions. 28–29. 284 with MAOIs. 156–157. 66–68. 346. 117–119. 279–280. 41–42. 165–166. 248 Dysthymic disorder. 115. 281. 15–16. 344. 368 Dexfenfluramine. 163–164 Ebastine. 162–163. 30. 348. 368 Diovan. 60–61. 349. 280 with paroxetine. 348. 190. 358. 279. 229–230. 195–196. 363. 356. 362 Desyrel. 203–204. 284 with bupropion. 365 Dienestrol. 72–73. 53–54. See Methadone Donepezil. See Phenytoin Dilaudid. 344. 347 L-Dopa. See Amitriptyline . 107–108. 192–193. 362 Dirithromycin. 279. 169–171. 348 Disulfiram. 178–179. 347. 368 Dolophine. 280. 368 Dogoxin. See Meperidine Depakote. See Hydromorphone Diltiazem. 279. 308. 362. See Fluconazole Diflunisal. 156–157. 368 Desmethyl metabolites. 346. 349 Diabetes mellitus. 80. 42–43. 348 Ecotrin. 80. 77–78. 295 with typical antipsychotics. 172–173. See Divalproex sodium Depression. 153. See Venlafaxine Elavil. 368 Digoxin. 360 Diazepam. 351. 78. 236–237 Desipramine. 52–53. 344. 280. 355. 362 Doxorubicin. 5–8 Duloxetine drug–drug interactions. 231–232. 58–60. 359 Drug–Drug Interaction Primer Divalproex sodium. 172–173. 365 Diclofenac. 352. 23–24. 365 Diethylcarbamate. 130–131. 101–102. 47–48. 314 with fluoxetine. 351. 27–28. 82–84. 160–161. 344. 111–112. 231–232 rashes. 210–211 Dermatology. 344 Dextromethorphan. See Aspirin Efavirenz. 123–124. 85–87. 309 pharmacokinetic features. 53–54. 346. See also Case Studies Index onychomycosis. 364.382 Demerol. 29–30. 209–210. See Trazodone Dexamethasone. 161–162. 109–111. 348. 357. 89–91 Doxepin. 368 Dopamine. 158–160. 276. 202–203. 49–50. 142–143. 180–181. 56–57. 347. 123–124. 344. 349. 76–77. 160–161. 279 with carbamazepine. 55. 279. 360. 243–275 patterns of P450 drug–drug interactions. 363 Digitoxin.

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

324 with pimozide. 285 with typical antipsychotics. 283–284. 231–232. 356. 287 with olanzapine. 368 drug–drug interactions. 60–61. 283. 354. 304 with risperidone. See Saquinavir Fractures. 336 . 25–26. 49–50. 283. 276. 351. 360. See Gastroesophageal reflux disease Gestodene. 34–35. 368 Flurbiprofen. 354 disorders. 355 Glomerulonephritis. 310 pharmacokinetic features. 324 with pimozide. 284. 344. 36–37. 310 Drug–Drug Interaction Primer interaction with caffeine. 354. See Ziprasidone GERD. 282. 354 Flutamide metabolite. 295 with typical antipsychotics. 55. 188–189. 220–221 Glucotrol. 198–199. 355 Grapefruit juice. 208 Ginseng. 285 with bupropion. 315 with clozapine. 285. 289 with phenytoin. 116. 351. 160–161. 300 with duloxetine. 362 Gabapentin. 281. See Generalized anxiety disorder Galactorrhea. 346. 282 with nefazodone. 368 interaction with atorvastatin. 124–125. 65–66. 283 with carbamazepine. See also individual foods charbroiled. 279. 133 Gemfibrozil. 282. 285. 184–185. 344. 354. See Glipizide Glyburide. 353. 341 pharmacokinetic features. 303 with phenytoin. 358. 284. 365 Garlic. 282. 355 Flutamide. 221–222 Frovatriptan. 300 with duloxetine. 282. 353 Furosemide. 355 Glipizide. 362 Generalized anxiety disorder (GAD). 119–120. 87–88. 353. 287 with alprazolam. 156–157 Gastrointestinal disease. 285. 307 with TCAs. 279. 209–210 GAD. 172 Glimepiride. 281 with MAOIs. 284 with haloperidol. 353. 247 Fluphenazine. 284 with mirtazapine. 334 with tobacco. 44–46.384 Fluoxetine (continued) drug–drug interactions (continued) with clozapine. 354. 95–96. 88–89. 356 Fluvoxamine. 35–36. 75–76. 295 with tertiary-amine TCAs. 302 with MAOIs. 151–152. 178–179. 362 Fluvastatin. 368 Gastroesophageal reflux disease (GERD). 347 Ganciclovir. 346. 279. 30 Fortovase. 283. 304 with TCAs. 172–173. 41–42. See also Anxiety disorder Geodon. 105–106. 331 with antipsychotics. 247 Food. 69–70 Galantamine. 46–47. 355. 99–101. 349 Ginkgo (Ginkgo biloba).

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

66–68. 171. 362–364 UGT2B. 250–251 Lanoxin. 107–185 International normalized ratio (INR). 348 Linezolid. 359 Isoniazid. 226–227 drug–drug interaction with ACE inhibitors and angiotensin II receptor antagonists. 349. 176. 355 Irinotecan. 42–43. 360 added to a substrate. See Clonazepam Labetalol. 346 added to a substrate. 351. 184 Irbesartan. 79–80. See Terbinafine Lamotrigine. 359. 316. 81–82. 368 Indocin. 88–89 Ketoconazole. 29–30. 124–125 Internal medicine. 362 drug–drug interactions with carbamazepine. 7 UGT1A. 358 Indoramin. See Digoxin Lansoprazole. 360 Itraconazole. 212–213 INR. 362. 368–369 reversal of. 158–160. 337 with loop diuretics. 119–120 Lescol. 360 2B6. 354. 7–8 substrated added to. 334 with oxcarbazepine. 322. 360 of 2D6. 5–6 description. 166–167 Lipitor. See also Case Studies Index case vignettes. 360 2B6. See Lamotrigine Lamisil. 344. 358. 91–92. 44–46. 165–166. 36–37. 203. 130–131. 2 P-glycoprotein. 368 Legionella pneumonia. 120–121. 357. 347. See Atorvastatin Lisinopril. 167–168. 321 with ethinylestradiol. 325 with sertraline. 359 Ketoprofen. 368 Isoflurane. 66–68. 321. 321. 355. 349. 362–364 UGT2B. 231–232. 226–227. 27–28. 25–26. 6 description. 368 Drug–Drug Interaction Primer Kava. 337 . 236–237. 346. 365 Induction toxicity. 61–62. 349. 351. 97–99. See Liver function tests Lidocaine. See Indomethacin Indomethacin. 357. 93–94. 351. 2 P-glycoprotein. 354. 365 Klonopin. 77–78. 368 Lilopristone. 204–206. 368 Ketones. 292. 93. See Fluvastatin Levomethadyl. 82–84. 74–75. 102–104. 76–77. 355. 356. 151. 7 UGT1A. See Sumatriptan Indinavir.386 Imitrex. 368–369 reversal of. 349. 322 with phenytoin. 349 LFTs. 235–236. 344 Inducers. See International normalized ratio Insomnia. 329 pharmacokinetic features. 365 Injuries. 127–129. 321 with valproate. 73–74. 165–166 Lithium. 77–78. 172. 362 Lamictal. 207–208. 118 Inhibitors.

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

18–19. 355. 289 with hydroxymethylglutaryl– coenzyme A reductase inhibitors. 353 drug–drug interactions. See N-acetyl-p-benzoquinone Naprosyn. 50–51. 289 with paroxetine. 365 Naloxone. 284. 351. 23–24. See Morphine MSIR. 292 with stimulants. 282. 362. 340 pharmacokinetic features. 353. 314–330 pharmacokinetic features. 288 with buspirone. 365. 286. 363. 336 with bupropion. 290 . 358 Monoamine oxidase inhibitors (MAOIs) drug–drug interactions. 18–19. 287. 347. 362. 282. 331 with atorvastatin. 284. 286 with TCAs. 202–203. 280. 101–102. John’s wort. 276. 197–199 Milk thistle. 173–174 Minaprine. 278. 315. 333 with citalopram. 284. 296 with venlafaxine. 363. 363. 325 pharmacokinetic features. 173–174 N-acetylcysteine. 27–28. 32–33. 287 with MAOIs. 365 Naltrexone. 248 Moclobemide. 248 Montelukast. 368 Moxifloxacin. 286 with bupropion. 153 Naftazone. 344 Mirtazapine. 363. 210–211. 282 with alprazolam. 316 with fluoxetine. 289. 316 with fluvoxamine. 298 with ziprasidone. 290 with sertraline. 288. 284 with mirtazapine. 336 with lovastatin. 301 with duloxetine. 125–126. 123–124. 336 with MAOIs. 312 interaction with St. 344. 363 Nefazodone. See Morphine Mucomyst. 288 with nefazodone. 333 with carbamazepine. 356. 221–222. 181–182 MS Contin. 220–221. 164–165.388 Migraine headaches. See N-acetylcysteine Myocardial infarction. 287. 161–162. See Naproxen Naproxen. 288. 280 with escitalopram. 44–46 drug–drug interactions. 282 with fluvoxamine. 349 Mood disorders. 288 with phenytoin. 368 drug–drug interactions. 354 Morphine. 177–178. 122–123. Slobodan. 81–82 Drug–Drug Interaction Primer Mood stabilizers. 278 with fluoxetine. 287–288 with carbamazepine. 250–251 Moricizine. 24–25. 218–219. 153 N-acetyl-p-benzoquinone (NAPQI). 352. 363. 66–68. 276 with buspirone. 365 Nardil. See Silymarin Milosevic. 344. 362. 347. 289 with paroxetine. 357 Modafinil. See Phenelzine Naringenin. 278 with clozapine. 362 Nalorphine. 365 NAPQI.

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

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

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

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

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

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

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

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

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

313 with typical antipsychotics. 313 with TCAs. See Olanzapine Zyvox. 347.398 Ziprasidone. 312. 347 Zyban. 29–30. 44–46. 312 with carbamazepine. 353. 311. See Bupropion Zyprexa. 365 Zonisamide. 353 drug–drug interactions. 287 with aripiprazole. 287. See Sertraline Zolpidem. 297. 313 pharmacokinetic features. 353 Zoloft. 305. 355 Zomepirac. 328 with pimozide. 320 with MAOIs. 250 Drug–Drug Interaction Primer Zocor. 348 Zopiclone. See Linezolid . 124–125. 187–188. 347. See Simvastatin Zolmitriptan. 312 with phenytoin. 312.

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