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Drug Metabolism and Related Drug Interactions

Marc Imhotep Cray, M.D

Cytochrome P450 oxidases are important enzymes in xenobiotic metabolism.
Learning Objectives
By the end of this presentation the learner will be able to:
1. Describe the different types of metabolic transformations that
drugs undergo and their physiological consequences.
2. Describe the potential changes in the chemical properties of a
drug metabolite versus the properties of the parent drug.
3. Discuss the concept that the effects of one drug can be modified
by the prior, or simultaneous, administration of a second drug.
4. Discuss the role that drug metabolism plays in mediating drug-
drug interactions.
5. Summarize the major mechanisms that can lead to drug-drug
interactions at the level of drug metabolism.
6. Discuss the role that enzyme induction and inhibition of
metabolic enzymes play in drug metabolism.
Marc Imhotep Cray, M.D. 2
Topics Outline
 Introduction
 Phase I metabolism
 Phase II metabolism (transferase reactions)
 Enzyme induction
 Enzyme inhibition
 Presystemic metabolism (“first-pass” effect)
 Metabolism of drugs by intestinal organisms
 Key Points Summary
 Case History and Discussion
NB: This presentation is intended for those learners who have completed the introduction
to PK and PD sequence, as knowledge of the concepts and mechanism discussed therein is
assumed.
Marc Imhotep Cray, M.D. 3
Introduction
 Drug metabolism (biotransformation) is metabolic breakdown
of drugs by living organisms usually through specialized
enzymatic systems
 More generally, xenobiotic metabolism (from Greek xenos "stranger"
and biotic "related to living beings") is set of metabolic pathways that
modify chemical structure of xenobiotics (compounds foreign to an
organism's normal biochemistry, such as drug or poison)
 Biotransformation reactions most often act to detoxify
poisonous compounds
 although in some cases intermediates in xenobiotic metabolism can
themselves cause toxic effects

Marc Imhotep Cray, M.D. 4
Introduction (2)
 Metabolism (biotransformation) of drugs-a
component of pharmacokinetics-is an important aspect
of pharmacology and medicine
For example:
 Rate of metabolism determines duration and intensity of a
drug's pharmacologic action
 Drug metabolism affects multidrug resistance in infectious
diseases and in chemotherapy for cancer
 Actions of some drugs as substrates or inhibitors of enzymes
involved in xenobiotic metabolism are a common reason for
hazardous drug interactions
Marc Imhotep Cray, M.D. 5
Introduction (3)
 Drug metabolism (biotransformation) is one of primary mechanisms by
which drugs are inactivated (=one form of drug eliminated)
 Examples include oxidation of phenytoin and ethanol
however,
 Not all metabolic processes result in inactivation drug activity is
sometimes ↑ by metabolism as in activation of prodrugs
 e.g. hydrolysis of enalapril to its active metabolite enalaprilat

 Formation of polar metabolites from a non-polar drug permits efficient
urinary excretion
however,
 Some enzymatic conversions yield active compounds with a longer half-life
than parent drug causing delayed effects of long-lasting metabolite as it
accumulates more slowly to its steady state
 e.g. diazepam has a half-life of 20–50 hours, whereas its pharmacologically active
metabolite desmethyldiazepam has a plasma half-life of approximately 100 hours
Marc Imhotep Cray, M.D. 6
Introduction (4)
Two phases drug metabolism
 It is useful to divide drug metabolism into two phases=
phases I and II  which often, but not always, occur
sequentially
 Phase I (non-synthetic) reactions involve a metabolic
modification of drug (commonly oxidation, reduction or
hydrolysis)
 Products of phase I reactions may be either pharmacologically
active or inactive

Marc Imhotep Cray, M.D. 7
Introduction (5)
Two phases drug metabolism cont.
 Phase II (synthetic) reactions are synthetic conjugation rxns
 Phase II metabolites have ↑polarity compared to parent drugs
and are more readily excreted in urine (or, less often, in bile),
and usually – but not always – pharmacologically inactive

 Molecules or groups involved in phase II reactions include
acetate, glucuronic acid, glutamine, glycine and sulfate may
combine w groups introduced during phase I metabolism
(=functionalization)
 For example, phenytoin is initially oxidized to 4-hydroxyphenytoin 
then glucuronidated to 4-hydroxyphenytoin-glucuronide readily
excreted via kidney
Marc Imhotep Cray, M.D. 8
Phase I Metabolism
Liver is most important site of drug metabolism
 Hepatocyte endoplasmic reticulum is most important but cytosol
and mitochondria are also involved

 Endoplasmic Reticulum
 Hepatic smooth endoplasmic reticulum contains cytochrome P450
(CYP450) enzyme superfamily (more than 50 different CYPs have been
found in humans) that metabolize foreign substances – “xenobiotics”,
i.e. medicinal drugs, pesticides, fertilizers and other chemicals
ingested by humans

 Metabolic reactions include oxidation, reduction and
hydrolysis
Marc Imhotep Cray, M.D. 9
P450 SYSTEM (cytochrome P-450-dependent
mixed-function oxidase system)
...“P450 system is a set of enzymes (usually hepatic, but not always) that
catalyze metabolism of a wide array of endogenous and exogenous
substances in order to detoxify them and then eliminate them from body.
These enzymes perform phase I, or oxidative, metabolism as opposed to
phase II conjugation. Each P450 enzyme is named by a number-letter-number
sequence (such as “1A2” or “3A4”). This sequence is rough equivalent of
“family, genus, species” as a way of identifying members of animal kingdom
and serves to identify specific P450 enzymes. 2C9 and 2C19 are more closely
related and share more common substrates than do 2C9 and 3A4. There are
more than 40 P450 enzymes”…
Guengerich FP: Role of cytochrome P450 enzymes in drug–drug interactions. Adv Pharmacol
43:7–35, 1997

Marc Imhotep Cray, M.D. 10
Approximate 50-60% of clinically used drugs are
metabolized by the CYP3A4 isoenzyme.

Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008.
Marc Imhotep Cray, M.D. 11
Phase I Metabolism: Oxidation
 Microsomal oxidation causes aromatic or aliphatic
hydroxylation, deamination, dealkylation or S-
oxidation
Reactions all involve
 Reduced nicotinamide adenine dinucleotide phosphate
(NADPH),
 Molecular oxygen, and
 One or more of a group of CYP450 haemoproteins which
act as a terminal oxidase in oxidation reaction (or can
involve other mixed function oxidases, e.g. flavin-
containing monooxygenases or epoxide hydrolases)
Marc Imhotep Cray, M.D. 12
Mechanism of reaction
In the overall reaction, drug is oxidized and oxygen is reduced
to water Reducing equivalents are provided by nicotinamide
adenine dinucleotide phosphate
(NADPH), and generation of this cofactor is coupled to
cytochrome P-450 reductase
 For example Overall reaction for aromatic hydroxylation
can be described as:

Marc Imhotep Cray, M.D. 13
Simplified model of cytochrome P450
mixed-function oxidase reaction sequence.
D is drug undergoing oxidation to produce DOH. Molecular oxygen serves as final electron
acceptor. Flavin protein cofactor (Fp) systems are involved at several sites. Iron of cytochrome
P450 is involved in binding oxygen and electron transfer with changes in valence state.

Wecker L, Crespo L , et al. Brody’s Human Pharmacology : Molecular to Clinical , 5th ed. Philadelphia, PA: Mosby-Elsevier, 2010.
Figure 2–7;22.
Marc Imhotep Cray, M.D. 14
Phase I Metabolism: Reduction & Hydrolysis
 Reduction
 Reduction requires reduced NADP-cytochrome-c
reductase or reduced NAD-cytochrome b5
reductase

 Hydrolysis
 Meperidine is de-esterified to meperidinic acid by
hepatic membrane-bound esterase activity

Marc Imhotep Cray, M.D. 15
Representative reduction and hydrolysis
reactions for metabolism of drugs.

Wecker L, Crespo L , et al. Brody’s Human Pharmacology : Molecular to Clinical , 5th ed.
Philadelphia, PA: Mosby-Elsevier, 2010. Figure 2–7;23.
Marc Imhotep Cray, M.D. 16
Phase I Metabolism
 Non-endoplasmic Reticulum Drug Metabolism
Oxidation
 Oxidation of ethanol to acetaldehyde is catalyzed by- cytosolic enzyme
–alcohol dehydrogenase whose substrates also include vitamin A
 Monoamine oxidase (MAO) is a membrane-bound mitochondrial
enzyme that oxidatively deaminates primary amines to aldehydes 
which are further oxidized to carboxylic acids or ketones
o Monoamine oxidase is found in liver, kidney, intestine and nervous tissue
o MAO substrates include catecholamines (dopamine, norepinephrine and
epinephrine), tyramine, phenylephrine and tryptophan derivatives (5-
hydroxytryptamine and tryptamine)
 Oxidation of purines by xanthine oxidase (e.g. 6-mercaptopurine is
inactivated to 6-thiouric acid) is non-microsomal

Marc Imhotep Cray, M.D. 17
Phase I Metabolism
 Non-endoplasmic Reticulum Drug Metabolism cont.
Reduction & Hydrolysis
 Reduction
This includes, for example, enzymatic reduction of double
bonds, e.g. methadone, naloxone

 Hydrolysis
o Esterases catalyze hydrolytic conversions of many drugs
• Examples include cleavage of suxamethonium by plasma
cholinesterase, an enzyme that exhibits pharmacogenetic variation
• hydrolysis of aspirin (acetylsalicylic acid) to salicylate, and
• hydrolysis of enalapril to enalaprilat
Marc Imhotep Cray, M.D. 18
Phase II Metabolism (Transferase Reactions)
Amino Acid Reactions
Glycine and glutamine are amino acids chiefly involved in
conjugation reactions in humans
 Glycine forms conjugates with nicotinic acid and
salicylate, whilst
 Glutamine forms conjugates with 4-aminosalicylate

 Hepatocellular damage depletes intracellular pool of these
amino acids thus restricting this pathway

 Amino acid conjugation is reduced in neonates
Marc Imhotep Cray, M.D. 19
Phase II Metabolism (2)
Acetylation
 Acetate derived from acetyl coenzyme A conjugates with
several drugs, including isoniazid, hydralazine and
procainamide

 Acetylating activity resides in cytosol and occurs in
leukocytes, gastrointestinal epithelium and liver (in reticulo-
endothelial rather than parenchymal cells)

Marc Imhotep Cray, M.D. 20
Phase II Metabolism (3)
Glucuronidation
 Conjugation reactions between glucuronic acid and carboxyl
groups are involved in metabolism of bilirubin, salicylates and lorazepam

 Some patients inherit a deficiency of glucuronide formation that
presents clinically as a nonhemolytic jaundice due to excess
unconjugated bilirubin = (Crigler–Najjar syndrome)
 Drugs that are normally conjugated via this pathway aggravate
jaundice in such patients

 O-Glucuronides formed by reaction with a hydroxyl group result in an
ether glucuronide
 This occurs with drugs such as acetaminophen and morphine

Marc Imhotep Cray, M.D. 21
Phase II Metabolism (4)
Methylation
Methylation proceeds by a pathway involving S-adenosyl
methionine as methyl donor to drugs w free amino, hydroxyl or
thiol groups

Catechol O-methyltransferase (COMT) is an example of such a
methylating enzyme is of physiological as well as
pharmacological importance
 COMT is present in cytosol, and catalyzes transfer of a methyl group
to catecholamines, inactivating norepinephrine, dopamine and
epinephrine

Marc Imhotep Cray, M.D. 22
Phase II Metabolism (5)
Methylation cont.
Phenylethanolamine N-methyltransferase (PNMT) is also
important in catecholamine metabolism
 It methylates terminal – NH2 residue of norepinephrine to form
epinephrine in adrenal medulla
 PNMT also acts on exogenous amines, including phenylethanolamine
and phenylephrine
 PNMT is induced by corticosteroids its high activity in adrenal
medulla reflects anatomical arrangement of blood supply to medulla
comes from adrenal cortex that contains very high concentrations of
corticosteroids

Marc Imhotep Cray, M.D. 23
Phase II Metabolism (6)
Sulfation
Cytosolic sulfonyltransferase enzymes= (SULTs) catalyze
sulfation of hydroxyl and amine groups by transferring a
sulfonyl group from 3’-phosphoadenosine 5’-phosphosulfate
(PAPS) to a xenobiotic
 Under physiological conditions, sulfonyltransferases generate
heparin and chondroitin sulfate
In addition, they produce ethereal sulfates
 From several estrogens, androgens
 From 3-hydroxycoumarin (a phase I metabolite of warfarin) and
 From acetaminophen
Are a number of sulfonyltransferases in hepatocyte w
different specificities
Marc Imhotep Cray, M.D. 24
Phase II Metabolism (7)
Mercapturic Acid Formation
Mercapturic acid formation is via reaction with cysteine residue in
tripeptide Cys-Glu-Gly, i.e. Glutathione
 Glutathione very important in acetaminophen (APAP) overdose when
usual sulfation and glucuronidation pathways of APAP metabolism are
overwhelmed resulting production of a highly toxic metabolite (N-
acetylbenzoquinoneimine, NABQI)

 NABQI is normally detoxified by conjugation with reduced
glutathione
 Availability of glutathione is critical in determining clinical outcome of
APAP toxicity
 Patients who have ingested large amounts of acetaminophen, thus
treated w thiol donors such as N-acetyl cysteine or methionine to
increase endogenous supply of reduced glutathione
Marc Imhotep Cray, M.D. 25
Phase II Metabolism (8)
Glutathione Conjugates
 Naphthalene and some sulfonamides also form conjugates w glutathione

One endogenous function of glutathione conjugation is
formation of a sulfidopeptide leukotriene, leukotriene (LT) C4
 Formed by conjugation of glutathione w LTA4 analogous to a phase
II reaction
o LTA4 is an epoxide which is synthesized from arachidonic acid by a
“phase I”-type oxidation reaction catalyzed by 5’-lipoxygenase
enzyme
o LTC4, together with LTD4, comprise activity once known as “slow-
reacting substance of anaphylaxis” (SRS-A) these LTs play a role
as bronchoconstrictor mediators in anaphylaxis and asthma
Marc Imhotep Cray, M.D. 26
Phases I and II of
drug metabolism

Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical
Marc Imhotep Cray, M.D. Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008. 27
A specific example of phases I and II of drug
metabolism: phenobarbital

Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London: Hodder
Arnold, 2008.

Marc Imhotep Cray, M.D. 28
Enzyme Induction
 Enzyme induction is a process by which enzyme activity is enhanced
usually b/c of ↑ enzyme synthesis (or, less often, reduced enzyme
degradation)
 ↑ in enzyme synthesis is often caused by xenobiotics binding to nuclear
receptors  which then act as positive transcription factors for certain
CYP450 isoenzymes
 There is marked inter-individual variability in degree of induction produced
by a given agent partly genetically determined

 Exogenous inducing agents include drugs, but also halogenated insecticides
(particularly dichloro-diphenyl-trichloroethane (DDT) and gamma-benzene
hexachloride), herbicides, polycyclic aromatic hydrocarbons, dyes, food
preservatives, nicotine, ethanol and hyperforin in St John’s wort
Marc Imhotep Cray, M.D. 29
Enzyme Induction (2)
A practical consequence of enzyme induction when two or
more drugs are given simultaneously if one drug is an inducing
agent it can accelerate metabolism of other drug may lead to
therapeutic failure

Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics
Marc Imhotep Cray, M.D. 5th Ed. London: Hodder Arnold, 2008. 30
Enzyme Inhibition
Allopurinol, methotrexate, ACE-I, NSAIDs and many others,
exert their therapeutic effects by enzyme inhibition
 Apart from such direct actions, inhibition of drug-
metabolizing enzymes by a concurrently administered drug
can lead to drug accumulation and toxicity
 For example, cimetidine, an antagonist at histamine H2-receptor,
also inhibits drug metabolism via CYP450 system and potentiates
actions of unrelated CYP450 metabolized drugs, such as warfarin
and theophylline
 Other potent CYP3A4 inhibitors include azoles (e.g. fluconazole,
ketoconazole) and HIV protease inhibitors (e.g. ritonavir)

Marc Imhotep Cray, M.D. 31
Enzyme Inhibition (2)

Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics
5th Ed. London: Hodder Arnold, 2008.

Marc Imhotep Cray, M.D. 32
Enzyme Inhibition (3)
Specificity of enzyme inhibition is sometimes
incomplete
 For example, warfarin and phenytoin compete with one
another for metabolism co-administration results in
elevation of plasma steady-state concentrations of both
drugs

Metronidazole is a non-competitive inhibitor of
microsomal enzymes  inhibits phenytoin, warfarin
and sulfonylurea (e.g. glyburide) metabolism

Marc Imhotep Cray, M.D. 33
Presystemic Metabolism (First-pass Effect)
Metabolism of some drugs is markedly dependent on route of
administration (RoA)

Following oral administration drugs gain access to systemic
circulation via portal vein so entire absorbed dose is exposed
first to intestinal mucosa then to liver before gaining
access to rest of body
 A considerably smaller fraction of absorbed dose goes through gut
and liver in subsequent passes b/c of distribution to other tissues and
drug elimination by other routes

Marc Imhotep Cray, M.D. 34
Presystemic Metabolism (2)
If a drug is subject to a high hepatic clearance (i.e. it is rapidly
metabolized by liver), a substantial fraction will be extracted from
portal blood and metabolized before it reaches systemic circulation
 This-in combination with intestinal mucosal metabolism- is known as
presystemic or “first-pass” metabolism

Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th
Marc Imhotep Cray, M.D. Ed. London: Hodder Arnold, 2008. 35
Mechanism of
presystemic clearance
 After drug enters enterocyte it can
undergo metabolism, excretion into
intestinal lumen, or transport into
portal vein
 Similarly, hepatocyte may accomplish
metabolism and biliary excretion prior
to entry of drug and metabolites to
systemic circulation
NB: P-glycoprotein is expressed on apical aspect of
enterocyte and on canaliculi aspect of hepatocyte.
It serves as a drug efflux pump, thus limiting availability
of drug to the systemic circulation. Roden MD. Principles of Clinical Pharmacology. In: Longo DL, Fauci AS, et al.
Harrison's Principles of Internal Medicine,18th Ed. New York, NY: McGraw-Hill,
2012. Figure 5-3; 35.
Presystemic Metabolism (3)
RoA and presystemic metabolism markedly influence pattern of
drug metabolism
For example,
 When salbutamol used for asthmatic ratio of unchanged
drug to metabolite in urine is 2:1 after IV administration
o But 1:2 after an PO dose
 Propranolol undergoes substantial hepatic presystemic
metabolism small doses given orally are completely
metabolized before they reach systematic circulation
o After IV administration, area under plasma concentration–time
curve (bioavailability) is proportional to dose administered and
passes through origin
Marc Imhotep Cray, M.D. 37
Propranolol AUC: PO vs IV
 Area under blood conc.–time curve
after PO and IV admin. of
propranolol to humans in various
doses
 T is apparent threshold for
propranolol following oral
administration
o After PO admin relationship, although
linear, does not pass through origin
o There is a threshold dose (T) below
which measurable concs. of
propranolol not detectable in
systemic venous plasma
Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical
Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008.

Marc Imhotep Cray, M.D. 38
Presystemic Metabolism (5)
 As explained in slide 35, presystemic metabolism is not limited to liver,
since GI mucosa contains drug-metabolizing enzymes  e.g. CYP3A4,
dopa-decarboxylase, COMT which can metabolize drugs, e.g. cyclosporine,
felodipine, levodopa, salbutamol, before they enter hepatic portal blood

 Pronounced first-pass metabolism by either GI mucosa (e.g. felodipine,
salbutamol, levodopa) or liver (e.g. felodipine, glyceryl trinitrate,
morphine, naloxone, verapamil) necessitates high oral doses by
comparison with the intravenous route

 Alternative routes of drug delivery (e.g. buccal, rectal, sublingual,
transdermal) partly or completely bypass presystemic elimination

Marc Imhotep Cray, M.D. 39
Presystemic Metabolism (6)
 Drugs undergoing extensive presystemic metabolism
usually exhibit pronounced inter-individual variability in
drug disposition results in highly variable responses to
therapy= one of major difficulties in their clinical use

 Next 2 slides provide examples of factors responsible for
variability in first-pass metabolism

Marc Imhotep Cray, M.D. 40
Presystemic Metabolism (7)
Variability in first-pass metabolism results from:
1. Genetic variations – for example bioavailability of hydralazine
is about double in slow compared to fast acetylators
 Presystemic hydroxylation of metoprolol and encainide also depends on
genetic polymorphisms (CYP2D6)

2. Induction or inhibition of drug-metabolizing enzymes

3. Food increases liver blood flow and can↑ bioavailability of
drugs e.g., propranolol, metoprolol and hydralazine, by ↑
hepatic blood flow and exceeding threshold for complete hepatic
extraction
Marc Imhotep Cray, M.D. 41
Presystemic Metabolism (8)
Variability in first-pass metabolism results from:
4. Drugs that increase liver blood flow have similar effects to food
For example, hydralazine↑ propranolol bioavailability by approx.
one-third, whereas
 Drugs that reduce liver blood flow (e.g. β-adrenoceptor antagonists)
reduce bioavailability
5. Non-linear first-pass kinetics are common (e.g. aspirin,
hydralazine, propranolol): ↑ dose disproportionately ↑
bioavailability

6. Liver disease ↑bioavailability of some drugs w extensive first-
pass extraction (e.g. diltiazem, cyclosporine, morphine)
Marc Imhotep Cray, M.D. 42
Metabolism of Drugs by Intestinal Organisms
 Metabolism of drugs by intestinal organisms
is important for drugs undergoing significant
enterohepatic circulation enterohepatic circulation
prolongs pharmacologic effect of some drugs
 For example, in case of estradiol excreted in bile as a
glucuronide conjugate bacteria-derived enzymes cleave
glucuronide  making free drug available for reabsorption
in terminal ileum small proportion of dose (approx.7%) is
excreted in feces under nml circumstances fecal excretion
increases if GI disease or concurrent antibiotic therapy alter
intestinal flora
Marc Imhotep Cray, M.D. 43
Enterohepatic circulation
 Substances (e.g., drugs) secreted
in bile may be absorbed by
intestinal epithelium and recycled
to liver via hepatic portal vein

Fox SI. Human Physiology 14th ed. New York, NY: McGraw-Hill, 2016.

Marc Imhotep Cray, M.D. 44
Key points
 Drug metabolism involves two phases: phase I often followed
sequentially by phase II
 Phase I metabolism introduces a reactive group into a molecule,
usually by oxidation, by a microsomal system present in liver
 CYP450 enzymes are a superfamily of hemoproteins. They have
distinct isoenzyme forms and are critical for phase I reactions
 Products of phase I metabolism may be pharmacologically
active, as well as being chemically reactive, and can be
hepatotoxic
 Phase II reactions involve conjugation (e.g. acetylation,
glucuronidation, sulfation, methylation)

Marc Imhotep Cray, M.D. 45
Key points
 Products of phase II metabolism are polar and can be
efficiently excreted by kidneys. Unlike products of phase I
metabolism, they are nearly always pharmacologically inactive
 CYP450 enzymes involved in phase I metabolism can be
induced by several drugs and nutraceuticals (e.g.
glucocorticosteroids, rifampicin, carbamazepine, St John’s
wort) or inhibited by drugs (e.g. cimetidine, azoles, HIV
protease inhibitors, quinolones, metronidazole) and dietary
constituents (e.g. grapefruit/grapefruit juice)
 Induction or inhibition of CYP450 system are important causes
of drug–drug interactions

Marc Imhotep Cray, M.D. 46
Case History
A 46-year-old woman is brought to the hospital emergency
department by her sister, having swallowed an unknown number
of acetaminophen tablets washed down with vodka six hours
previously, following an argument with her boyfriend. She is an
alcoholic and has been taking St John’s wort for several weeks.
Apart from signs of intoxication, examination was unremarkable.
Plasma acetaminophen concentration was 662 μmol/L (100 mg/L).
Following discussion with the medical resident and Poison Control,
it was decided to administer N-acetylcysteine.
NB: A plasma acetaminophen concentration of 100 mg/L six hours after
ingestion would not usually require antidote treatment.
Question: Why was it decided to administered N-acetylcysteine in this case.
Marc Imhotep Cray, M.D. 47
Acetaminophen (APAP) poisoning case discussion
Acetaminophen may cause severe liver damage if 12g (24
tablets) or > 150mg APAP/kg body weight are taken
 Some patients have risk factors for enhanced toxicity (see below) and
may be at risk if > 75mg/kg has been taken

Pathogenesis:
A metabolite of APAP (N-acetyl-p-benzoquinoneimine = NAPQI)
binds glutathione in liver and causes hepatic necrosis when
stores of glutathione are exhausted
 usual pathway of elimination is overwhelmed and NABQI (highly
hepatotoxic) is formed by CYP1A2, 2E1 and CYP3A4 metabolism
Renal failure from ATN can also occurs  renal failure without
liver failure is rare
Marc Imhotep Cray, M.D. 48
APAP poisoning case discussion cont.
Risk factors for acetaminophen toxicity:
Alcoholics and patients on drugs that induce hepatic enzymes
are at greater risk of toxicity b/c of ↑ production of toxic
metabolite of APAP
 some relevant drugs are anticonvulsants, rifampin, and St John’s
wort

Patients with malnutrition, anorexia, cachexia or HIV infection
may have ↓ glutathione stores and be at ↑ risk of liver
damage

Marc Imhotep Cray, M.D. 49
Case History Comments
 As indicated above, a plasma acetaminophen concentration of
100 mg/L six hours after ingestion would not usually require
antidote treatment but this woman is an alcoholic and is
taking St John’s wort and her hepatic drug-metabolizing
enzymes (CYP1A2, CYP3A4 and probably others) will have been
induced so APAP conc. threshold for antidote treatment is
lowered

 N-Acetylcysteine is specific antidote, as it increases reduced
glutathione which conjugates NABQI within hepatocytes

Marc Imhotep Cray, M.D. 50
THE END

See next slide for further study tools and resources.
51
Companion study tools:
 MedPharm Syllabus| Digital Guidebook 2015: Unit 1: General Principles of
Pharmacology string (Pgs. 10-29).
 PK video mini-lectures, tutorials and textbook

Sources and further study:
 Longo DL, Fauci AS, et al. Harrison's Principles of Internal Medicine, 18th Ed. New
York, NY: McGraw-Hill, 2012.
 Lyubimov VA (Ed.) Encyclopedia of Drug Metabolism and Interactions, 6-Volume Set,
1st ed. Hoboken, NJ: John Wiley & Sons, 2012.
 Pearson PG, Wienkers LC (Eds.) Handbook of drug metabolism. 2nd ed. New York, NY:
Informa Healthcare, 2008.
 Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and
Therapeutics 5th ed. London: Hodder Arnold, 2008.
 Wecker L, Crespo L , et al. Brody’s Human Pharmacology : Molecular to Clinical , 5th
ed. Philadelphia, PA: Mosby-Elsevier, 2010.

Marc Imhotep Cray, M.D. 52