Drug Metabolism and Related Drug Interactions by Marc Imhotep Cray, M.D.

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 drugdrug 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Phase I Metabolism: Oxidation  Microsomal oxidation causes aromatic or aliphatic hydroxylation, deamination, dealkylation or Soxidation 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. flavincontaining monooxygenases or epoxide hydrolases) Marc Imhotep Cray, M.D.

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.

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. Brodyâ&#x20AC;&#x2122;s Human Pharmacology : Molecular to Clinical , 5th ed. Philadelphia, PA: Mosby-Elsevier, 2010. Figure 2â&#x20AC;&#x201C;7;22.

Marc Imhotep Cray, M.D.

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.

Representative reduction and hydrolysis reactions for metabolism of drugs.

Wecker L, Crespo L , et al. Brodyâ&#x20AC;&#x2122;s Human Pharmacology : Molecular to Clinical , 5th ed. Philadelphia, PA: Mosby-Elsevier, 2010. Figure 2â&#x20AC;&#x201C;7;23.

Marc Imhotep Cray, M.D.

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 (5hydroxytryptamine 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.

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.

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.

Phase II Metabolism (2) Acetylation ď ą Acetate derived from acetyl coenzyme A conjugates with several drugs, including isoniazid, hydralazine and procainamide ď ą Acetylating activity resides in cytosol and occurs in leukocytes, gastrointestinal epithelium and liver (in reticuloendothelial rather than parenchymal cells)

Marc Imhotep Cray, M.D.

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.

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.

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.

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.

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 (Nacetylbenzoquinoneimine, 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.

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 “slowreacting substance of anaphylaxis” (SRS-A) these LTs play a role as bronchoconstrictor mediators in anaphylaxis and asthma Marc Imhotep Cray, M.D.

Phases I and II of drug metabolism

Marc Imhotep Cray, M.D.

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

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.

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.

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

Marc Imhotep Cray, M.D.

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

Enzyme Inhibition Allopurinol, methotrexate, ACE-I, NSAIDs and many others, exert their therapeutic effects by enzyme inhibition  Apart from such direct actions, inhibition of drugmetabolizing 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.

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.

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.

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.

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

Marc Imhotep Cray, M.D.

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

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.

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.

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.

Presystemic Metabolism (6) ď ą Drugs undergoing extensive presystemic metabolism usually exhibit pronounced inter-individual variability in drug dispositionď&#x192; results in highly variable responses to therapy= one of major difficulties in their clinical use ď ą Next 2 slides provide examples of factors responsible for variability in first-pass metabolism

Marc Imhotep Cray, M.D.

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.

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 firstpass extraction (e.g. diltiazem, cyclosporine, morphine) Marc Imhotep Cray, M.D.

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.

Enterohepatic circulation ď&#x201A;§ 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.

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.

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.

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 Johnâ&#x20AC;&#x2122;s wort for several weeks. Apart from signs of intoxication, examination was unremarkable. Plasma acetaminophen concentration was 662 Îźmol/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.

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.

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.

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.

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.