COMPREHENSIVE
`PHARMACy REviEw
`
`_
`
`|]l__'_.l
`
`_
`
`Leon Shargel
`Paul F. Souney
`
`Alan H. Mutnick
`Larry N. Swanson
`
`it .W0lters Kluwer Lippincott
`““‘”‘
`Williams & Wilkins
`
`thCPO1n';"‘:
`
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`

`
`7th edition
`
`comprehens_|ve
`pharmacy review
`
`EDITORS
`
`Leon Shargel, PhD, RPh
`Alan H. Mutnick, PharmD, FASHP, RPh
`Paul F. Souney, MS, RPh
`Larry N. Swanson, Pharml), FASHP, RPh
`
`®. Wolters Kluwer Lippincott Williams & Wilkins
`Heanh
`Philadelphia - Baltimore - New ‘i'ork- London
`Buenos Aires - Hang Kung ‘ Sydney - Tokyo
`
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`
`Acquisitions Editor: John Goucher
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Christen D. Murphy
`Project Manager: Paula C. Williams
`Designer: Doug Smock
`Production Services: Maryland Composition, Inc.
`Seventh Edition
`
`Copyright © 201 O, 2007, 2004, 2001 by Lippincott Williams 8: Wilkins, a Wolters Kiuwer business.
`351 WestCamden Street
`530 Walnut Street
`Baltimore, MD 2i201
`Philadelphia, PA191D6
`Printed in the United States of America
`
`All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in
`any form or by any means, including as photocopies or scanned—in or other electronic copies, or utilized by any
`information storage and retrieval system without written permission from the copyright owner, except for brief
`quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as
`part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To
`request permission, please contact Lippincott Williams «Sc Wilkins at 530 Walnut Street, Philadelphia, PA 19106,
`via email at ,oermJ'ssions@lww.com, or via website at |ww.com (products and services).
`9 8 7 6 5 4 3 2
`1
`
`Library of Congress Cataloging-in-Publication Data
`
`Comprehensive pharmacy review r’ editors, Leon Shargel
`p. ; cm.
`Includes index.
`ISBN 978-168255-711-3
`
`[et al.I.—7th ed.
`
`1. Pharmacy—Examinations, questions, etc.
`tions. QV 18.2 C737 20091
`RS97.P49 2009
`615'.1076—dc22
`
`I. Shargel, Leon, 1941-IDNLM: 1. Pharmacy—Examination Ques-
`
`DISCLAIMER
`
`2008035490
`
`Care has been taken to confirm the accuracy of the information present and to describe generally accepted
`practices. However, the authors, editors, and publisher are not responsible for errors or omissions or for any conse-
`quences irom application of the information in this book and make no warranty, expressed or implied, with respect
`to the currency, completeness, or accuracy of the contents of the publication‘ Application of this information in a
`particular situation remains the professional responsibility of the practitioner; the clinical treatments described and
`recommended may not be considered absolute and universal recommendations.
`The authors. editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in
`this text are in accordance with the current recommendations and practice at the time of publication. However, in
`view of ongoing research, changes in government regulations, and the constant flow of information relating to drug
`therapy and drug reactions, the reader is urged to checlcthe package insertfor each drug for any change in indications
`and dosage and for added warnings and precautions. This is particularly important when the recommended agent
`is a new or infrequently employed drug.
`‘
`Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA) clearance
`for limited use in restricted research settings. It is the responsibility of the health Care Piovider to ascertain the FDA
`status of each drug or device planned for use in their clinical practice‘
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`
`17
`Drug Metabolism, Prodrugs,
`and Pharmacogenetlcs
`Marc W. Harrold
`
`I. INTRODUCTION TO DRUG METABOLISM. Drug metabolism (also called biotransforma-
`tion) refers to the biochemical changes that drugs and other foreign chemicals (xenobiotics)
`undergo in the body, leadingto the formation ofdifferent metabolites with different effects. Xenobi—
`otics can undergo a variety of biotransformation pathways, resulting in the production of a mixture
`of intermediate metabolites and excreted products, including unchanged parent drug. Rarely is
`only one metabolite produced from a single drug.
`
`A. Inactive metabolites. Some metabolites are inactive (i.e., their pharmacologically active parent
`compounds become inactivated or detoxified).
`1. The hydrolysis of procaine to p—aminoben2oic acid and diethylethanolamine results in a
`loss of anesthetic activity.
`
`2. The oxidation of 6-mercaptopurine to 6-mercapturlc acid results in a loss of anticancer
`activity.
`
`Metabolites that retain similar activity. Certain metabolites retain the pharmacological activity
`of their parent compounds to a greater or lesser degree.
`1. lmipramine isdemethylated to the essentially equiactive antidepressant, desipramine.
`2. Acetohexarnide is reduced to the more active hypoglycemic, I-hydroxyhexamide.
`
`3. Codeine is demethylated to the more active analgesic, morphine.
`
`Metabolites with altered activity. Some metabolites develop activity different from that of their
`parent drugs.
`1. The antidepressant iproniazid is dealkylated to the antitubercular, isoniazid.
`2. The vitamin retinoic acid (vitamin A) is isomerizecl to the anti-acne agent, isoretinoic acid.
`
`Bioactivated metabolites. Some pharmacologically inactive parent compounds are converted
`to active species within the body. These parent compounds are known as prodrugs.
`1. The prodrug enalapril is hydrolyzed to enalaprilat, a potent antihypertensive.
`2. The prodrug sulindac, a sulfoxide, is reduced to the active sulfide.
`3. The antiparlcinsonian levodopa (I.-dopa] is decarboxylated in the neuron to active dopa-
`mine.
`
`II. BIOTRANSFORMATION PATHWAYS
`
`A. Phase I reactions are those in which polar functional groups are introduced into the molecule
`or unmasked by oxidation, reduction, or hydrolysis.
`1. Oxidation is the most common phase l biotransformation.
`a. The majority of oxidations occur in the liver; however, extrahepatic tissues, such as the
`intestinal mucosa, lungs, and kidney, can also serve as metabolic sites.
`b. The vast majority of oxidations are catalyzed by a group of mixed—function oxidases
`known as cytochrome P450 (CYP450). These oxldases are bound to the smooth endoplas-
`tic reticulum of the liver and require both NADPH and a porphyrin prosthetic group.
`Unlike most enzymes, CYP-450 uses a variety of oxidative biotransforrnations to metabol-
`ize a diverse group of substrates.
`
`398
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`Drug Metabolism, Prodrugs, and Pharmacogenetics
`
`399
`
`c. CYP45O exists in multiple isoiorms or families. The presence ofthese different isoforms
`is responsible for the large substrate variation seen with CYP450.
`(1) 'CYP45O isoforms are named using the root "CYP” followed by an arabic number
`designating the family, a letter designating the subfamily, and a second arabic num-
`ber indicating the individual gene (e.g., CYP3A4).
`(2) Six mammalian families are involved in steroid and bile acid metabolism: CYP7,
`CYP11, CYP17, CYP19, CYP21, and CYP27.
`.
`(3) Four mammalian families are involved in xenobiotic, or drug, metabolism: CYP1,
`CYP2, CYP3, and CYP4. Examples ofdrugs metabolized bythesefamilies andsubfam-
`ilies are shown in Table 1 7-1. Note that a number ofdrugs (e.g., tricyclic antidepres-
`sants, diazepam, ondansetron, theophyllinej are metabolized by multiple isoforms.
`d. Additional oxidations (e.g., ethanol to acetaldebyde) are catalyzed by nonmicrosomal
`oxidases located in cytosol and mitochondria of extrahepatic tissues.
`9. CYP450 and nonmicrosomal oxidases catalyze aromatic, aliphatic, olefinic, benzylic,
`allylic, and u.-hydroxylations; N-, O—, and 5-dealkylations; oxidative deamination;
`N- and 5-oxidations; desulfuration; dehalogenation; and oxidations of alcohols and
`aldehydes (Table 17-2).
`1''. The increased polarity of the oxidized products (metabolites) enhances their water solu-
`bility and reduces their tubular reabsorption to some extent, thus favoring their excretion
`in the urine. These metabolites are somewhat more polar than their parent compounds
`and very commonly undergo further biotransformation by phase ll pathways (see II B).
`2. Reduction is less ‘commonly encountered than oxidation; however, the overall goal is the
`same: to create polar functional groups that can be eliminated in the urine, There is evidence
`suggesting that the CYP450 system might be involved in some reductions. Additionally,
`bacteria resident in the GI tract are known to be involved in azo and nitro reductions.
`Reactions catalyzed by reductasesare shown in Table 17-3.
`3. Enzymatic hydrolysis, the addition of water across a bond, also results in more polar metabo-
`lites (see Table 17-3).
`a. Esterase enzymes, usually present in plasma and various tissues, are nonspecific and
`catalyze cle-esterification, hydrolyzing relatively nonpolar esters into two polar, more
`water-soluble compounds: an alcohol and an acid. Esterases are responsible for convert-
`ing many prodrugs into their active forms.
`b. Amidase enzymes hydrolyze amides into amines and acids (deamidation). Deamidation
`occurs primarily in the liver.
`c. Ester drugs susceptible to plasma esterases (e.g., procaine) are usually shorter acting
`than structurally similar amide drugs (e.g., procainamide), which are not significantly
`hydrolyzed until they reach the liver.
`d. Lactones and Iaciams are cyclic esters and amides, respectively, and are thus also sus-
`ceptible to hydrolytlc metabolism.
`
`B. Phase [I reactions are those in which the functional groups of the original drug (or metabolite
`formed in a phase I reaction) are masked by a conjugation reaction. Most phase [I conjugates
`are very polar, resulting in rapid drug elimination from the body,
`1. Conjugation reactions combine the parent drug (or its metabolites) with certain natural
`endogenous constituents, such as glucuronic acid, glycine, glutamine, sulfate, glutathione,
`the two—carbon acetyl fragment, or the one-carbon methyl fragment. These reactions gener-
`ally require both a high-energy molecule and an enzyme.
`a. The high-energy molecule consists of a coenzyme bound to the endogenous substrate,
`the parent drug, or the drug’s phase 1 metabolite.
`b. The enzymes (called transferases) that catalyze conjugation reactions are found mainly
`in the liver and, to a lesser extent, in the intestines and other tissues.
`c. Most conjugates are highly polar and unable to cross cell membranes, making them
`almost always pharmacologically inactive and of little or no toxicity. Exceptions to this
`are acetylatedand methylated conjugates. These conjugates do not possess increased
`polarity; however, they are usually pharmacologically inactive.
`2. There are six conjugation pathways (Table 17-4).
`a. Glucuronidation is the most common conjugation pathway because of a readily avail-
`able supply of glucuronic acid as well as a large variety of functional groups, which
`can enzymatically react with this sugar derivative.
`
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`
`400
`
`Chapter 77 H B
`
`me P450 (CYP) lsoforms
`
`Table 17-1. Examples of Drugs Metabolized by Specific Cytochro
`CYP1A2
`CYPZDB
`CYP3A4
`Acetaminophen
`Amitriptyline and
`Acetaminophen
`Amitriptyline and
`other TCA5
`Alfentanil
`other TCAS
`|3—blockers
`Benzodiazepines
`Diazeparn
`Benztropine
`Amitriptyline and
`Methadone
`Captopril
`other TCAs
`Olanza ine
`Chlor heniramine
`Amiodarone
`P
`P
`Propranolol
`Chlorpromazine
`Anastrazole
`Riluzole
`Clemastine
`Azole antifungals
`Tacrine
`Clozapine
`Buspirone
`Theophylline
`Codeine
`Busulfan
`CYWB1
`Delavirdine
`Carbamazepine
`Chlorpheniramine
`Dextromethorphan
`Chlorpromazine
`Diphenhydramine
`Cimetidme
`CYPZB5
`Dolasetron and
`Clozapine
`_
`B“PV°Pl0“
`Ondansetron
`Codeine
`CYCl°Pl‘05Pl‘am'de
`Donepezil
`Cyclophosphamide
`and llosfamlde
`Encainide
`and ifosfarnide
`cypgcg
`Fenfluramine
`Cyclosporin
`Diazepam
`Fentanyfl
`Dapsone _
`Didofenac
`Flecaimde
`Darifenacin
`Mephobarbitai
`Fluphenazine
`Delavirdine
`Omeprazole
`Hydrocodone
`Dexamethasone
`pac|itaxe|
`Hy‘droxy_zine
`Dextromethorphan
`Retmoids
`lmipramine
`Dihydroergotamine
`Tojbutamrde
`ll:|('.lGCaéI_1E
`Dll(’!‘ydTOF?%/Ttlfllfl-ES]
`orata me
`l.E'.,
`l‘Il e ipine
`CYEZFB.
`1,
`Meperidine
`Diltiazem
`m'lr:'ptl_|’_'C':f an
`Methadone
`Disopyramide
`01 er
`Methamphetamine
`Docetaxel and
`_
`5
`.
`(C:hl°rl';.l|el|l"am'ne
`Mexiletine
`paclitaxel
`awe ' 0
`Morphine
`Dolasetron and
`Dapsone
`Ondansetron
`ondansetron
`.
`.
`.
`ycodone
`Donepezil
`Diazepam
`Ox
`-
`.
`Sllmipllglel
`Risperidone
`Doxorubicin
`Lem ar
`Selegiline
`Efavirenz
`lta
`N°S5:TtD5l”
`SSR!s
`Enalapril
`5.
`Tamoxifen
`Ergot alkaloids
`ghillllolrld
`Thioridazine
`Erlotinib
`To “lair e
`Tolterodine
`Estrogens
`Vorsen" .el
`Tramadol
`Ethosuxirnide
`m?r:,pa.ml
`Trazodone
`Etoposide
`3‘. 3"“
`Erythromycin and
`Zamlukasl
`cY:2El
`-
`clarithromycin
`h
`cetammop en
`Felbamate
`Eglggglate
`Fentanyl
`General anesthetics
`Flexofenlldlne
`-
`-
`Finasteride
`lsomazid
`Ondansetron
`Elutgmlilie
`Tamoxifen
`V ll" e
`Theophyn-me
`Gramsetron
`HMC Co/1, [3-hydroxy-[5-methylglutaryl—coenzyme A; NSAIDS, nonsteroidal anti-inflammatory drugs; $.S'Rl's, selective
`serotonin reuptalce inhibitors; TCAS, tricyclic antidepressants.
`
`d
`
`CYP3A4 (cont)
`Haloperidol
`HIV protease
`inhibitors
`HMG-CoA reductase
`inhibitors
`Hydrocodone
`Hydrocortisone
`Irinotecan
`Lansoprazole
`Liclocaine
`Loperamide
`Loratadine
`Losartan
`Midazolam
`Mifepristone
`Navelbine
`Nefazodone
`Nevirapine
`Norethisterone
`Omeprazole
`‘
`Ondansetron
`Oral contraceptives
`Qxybdtynin
`Pimozide
`_Predn&so_ne‘and
`pre niso one
`Quinidine
`Repaglinide
`Rifampin and
`analogs
`Risperidone
`Salmeterol
`Sildenafii
`.
`.
`SSR!5
`Sulfamethoxazole
`Tacrolimus
`Tadalafil
`Tamoxifen
`Teniposide
`Testosterone
`Theophylline
`Tolterodine
`Tretinoin
`.
`.
`Valproic acid
`Vardenafil
`.
`Vherapamll
`Vinca alkaloids
`.
`Warlann
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`
`Drug Metabolism, Prodrugs, and Pharmacogenetics
`
`401
`
`Table 17-2. Phase I Metabolism: Oxiclative Pathways
`Type of Reaction (Examples)
`Reaction Pathway
`1.
`1 .
`
`Aromatic Hyclroxylation
`(phenytoin, phenylbutazone)
`
`2’
`
`3.
`
`R/‘x/DH:
`
`j-D
`
`R _ K
`
`*—"
`
`HD
`
`R
`
`OH
`
`on
`
`R
`
`4_ R CH_ —-—-5 R CfiOH
`
`R/\-?\CH, j’ R/‘\7\C1'E0H
`
`on
`:11
`ll}
`R1’ \n/\R= *9 R: W/kn‘
`o
`0
`o
`
`R/\|’NH:
`CH,
`
`---—>
`
`{Y
`CH;
`
`p.—§—cu,
`
`jun
`
`R-NH;
`
`H
`1;,‘ _.
`(311.
`
`4*“
`
`‘'31’!
`A‘
`
`A’
`
`C“:
`
`R—o—c[-1. *
`
`11-OH
`
`2. Aliphatic Hydroxylation
`lpentobarbital, meprobamate]
`
`3. Olefini-: Hydroxylation
`(carbamazepine, cyproheptadine}
`
`4. Benzylic Hydroxylation
`(tolbutamide, imipramine)
`
`5. Allylic Hydroxylation
`(pentazocine, hexobarbital)
`
`6. Hydroxylation-oitoaCarbonyl
`(cliazepam, ketamine)
`
`7. Oxidative Deamination '
`(amphetamine, dopamine)
`
`3. N-Dealkylation
`(morphine, ephedrine)
`
`9. N-Oxidation
`(acetaminophen, guanethidine)
`
`10. O-Dealkylation
`(codeine, papaverine)
`11. 5«Dealky|ation
`(6-methylmercaptopurine)
`‘[2. Sflxidation
`(chlorpromazine, mesoridazine)
`
`'
`
`13. Desulfuration
`(thiopental)
`
`14. Dehalogenation
`(halothane, chloramphenicol)
`
`15. Oxidation of Alcohols
`(ethanol, estradioli
`16. Oxidation of Aldehydes
`lacetaldehyde, PGE2)
`
`5.
`
`6.
`
`7_
`
`8.
`
`9_
`
`10.
`
`ll.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16,
`
`R—s—-CH, eh 1—5H
`O
`/Isl‘
`
`A125-xx —:—b
`
`5
`
`3-.’
`
`ll Th
`‘R;
`c1
`cp,—l—}1 —:p
`B,
`
`A’
`
`19/
`
`CI
`
`'5!‘
`
`°F,—‘€
`
`R
`
`PV
`0
`
`H
`
`R—cHzQH
`
`-—-jp
`
`R_cH¢ __,
`
`R—CH0
`
`1L—co,H
`
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`
`402
`
`Chapter F7 H B
`
`Table 17-3. Phase 1 Metabolism: Reductive and Hydrolytic Pathways
`Type of Reaction (Examples)
`Reaction Pathway
`Reduction
`0
`1. Carbonyl Reduction
`[acetohexamidel
`R,)kR=
`
`1'
`
`I
`
`OH
`R,)\R.2
`
`2. Azoreduction
`(sulfasalazine, olsalazine)
`
`2_ R, N‘
`mos
`
`a,—C>—m
`
`0;N©—R ———|> ENQR
`0
`KJLOH
`
`0
`Ru)L0'
`
`K
`‘
`
`+
`
`no—1u
`
`3. Nitroreduction
`(chloramphenicol, clonazepam)
`
`Hydrolysis
`4. Ester Hydrolysis
`(procaine, meperidine)
`
`5. Amide Hydrolysis
`(lidocaine, indomethacin)
`
`3,
`
`4.
`
`5.
`
`)l\ .12,
`
`R
`
`RAD“
`
`* ”*»“'“:
`
`(1) The high-energy form of glucuronic acid, uridine diphosphate glucuronic acid,
`reacts with a variety of functional groups under the influence of glucuronyl trans-
`ferase.
`(2) Drugs thatpossess hydroxyl or carhoxyl functional groups readily undergo glucuron—
`idation to form ethers and esters, respectively. In addition, N-, 5-, and Cglucuronides
`are also possible.
`(3) As shown in Table 17-4, the addition of glucuronic acid to a drug molecule adds
`three hydroxyl groups and one carboxyl group. This addition greatly increases the
`hydrophilicity of the drug molecule. As a result,
`it
`is unlikely to penetrate cell
`membranes and elicit pharmacological activity. It is also poorly reabsorbed by the
`renal tubules and, thus, is readily excreted.
`(4) Clucuronides with high molecular weight [more than 500) are often excreted into
`the bile and, eventually, into the intestines. The intestinal enzyme B-glucuronldase
`can then hydrolyze the conjugate, releasing the unaltered drug (or its primary metab-
`olite) for reabsorption by the intestine.
`b. Sulfate conjugation is much less common than glucuronide conjugation because
`there is no available pool of endogenous sulfate. Additionally, there are fewer func-
`tional groups capable of forming sulfate conjugates. The high-energy form of sulfate,
`3’-phosphoadenosine-5’-phosphosulfate (PAPS), reacts with phenols, alcohols, ary|arn-
`ines, and N—hydroxyl compounds under the influence of sulfotransferase to form highly
`polar metabolites.
`:2. Amino acid conjugation involves the reaction of either glycine or glutamine with all-
`phatic or aromatic acids to form amides. A drug molecule is first converted to an acyl
`coenzyme A intermediate. An N—acyltransferase enzyme then catalyzes the conjugation
`of the activated drug molecule with the amino acid.
`cl. Glutathione conjugation is extremely important in preventing toxicity from a variety of
`harmful electrophilic agents. Clutathione, a tripeptide containing a nucleophilic su|fhy-
`dryl group, is present in almost all mammalian tissues. Under the influence of glutathione
`S—transferase, glutathione can reactwith halides, epoxides, and other electrophilic com-
`pounds to form harmless inactive products. When glutathione has reacted with an elec-
`trophile,
`it undergoes a series of reactions to produce a mercapturic acid derivative,
`which is eliminated.
`
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`
`Drug Metabolism, Prodrugs, and Pharmacogenetics
`
`403
`
`Table 17-4. Phase I] Metabolism: Conjugation Pathways
`Reaction Pathway
`R = Drug Molecule; X = Functional Group
`
`Type of Conjugate
`
`1.
`
`Glucuronide
`(X = OH, NR2. co2H,
`SH, acidic carbon atoms)
`
`1_
`
`H0;C
`0
`Home
`"0
`H00
`‘UDP
`
`*
`
`l-I01C
`
`H0
`R X
`T T’ HO
`
`0
`
`HO
`
`H
`
`x
`
`‘R
`
`. Sulfate
`(X = OH, arylamines,
`NH—OH)
`
`2
`
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`(X = electrophilic center
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`(X = OH, NH2, SH)
`
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`(X = NH;, NHNH2,
`SO2NH2, CO__NH2)
`
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`e. Methylation of oxygen-, nitrogen-, and sulfur-containing functional groups results in
`metabolites that are usually less polar than the unaltered drugs. Methylation can inacti-
`vate Certain Compounds [e.g., catechol O»methy| transferase (COMT) methylates a num-
`ber of catecholamine neurotransmitters], but overall it plays a minor role in the elimina-
`tion of drugs.
`its major role is
`in the biosynthesis of endogenous compounds (e.g.,
`epinephrine). The high-energy form required for methyltransferase enzymes is S-adeno~
`sylmethionine (SAM).
`. Acetylation can occur with primary amines, bydrazides, sulfonamides, and, occa5lon~
`ally, amides.
`It leads to the formation of N-acetylated products. These products are
`usually less polar than the unaltered drug and can retain pharmacological activity.
`(1) N-acetylated metabolites can accumulate in tissue or in the kidneys, as in the case
`of certain antibacterial sulfonamides. Crystalluria and subsequent tissue damage
`may result.
`(2) The high—energy molecule for acetylation is acetyl-CUA. The reaction is catalyzed
`by N—acetyltransferase.
`
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`404
`
`Chapter 17 H! A
`
`III. FACTORS INFLUENCING DRUG METABOLISM
`
`A. Chemical structure specifically influences a drug‘s metabolic pathway. The presence or ab-
`sence of cermi n functional groups will determine the necessity, route, and extent of metabolism.
`
`B. Species differences
`1. Qualitative differences in the actual metabolic pathway. Such a variation can result from
`a genetic deficiency of a particular enzyme or a difference in a particular endogenous
`substrate. In general, qualitative differences occur primarily with phase II reactions.
`--2. Quantitative differences are differences in the extent to which the same type of metabolic
`reaction occurs. Such a variation can result from a difference in the enzyme level, the
`presence of species specific isozymes, a difference in the amount of endogenous inhibitor
`or inducer, or a difference in the extent of competing reactions. In general, quantitative
`differences occur primarily with phase I reactions.
`
`C. Physiological or disease state
`1. Because the liver is the major organ involved in biotransformation, pathological factors
`that alter liver function can affect a drug's hepatic clearance.
`2. Congestive heart failure decreases hepatic blood flow by reducing cardiac output, which
`alters the extent of drug metabolism.
`3. An alteration in albumin production (the p|asma’s major drug-binding protein) can alter
`the fraction of bound to unbound drug. Thus, a decrease in plasma albumin can increase
`the fraction of unbound (free) drug, which then becomes available to exert a more intense
`pharmacological effect. The reverse is true when plasma albumin increases.
`D. Genetic variations
`
`1. The acetylation rate depends on the amount of N—acety|transferase present, which is deter-
`mined by genetic factors. The general population can be divided into fast acetylators and
`slow acetylators. For example, fast acetylators are more prone to hepatotoxicity from the
`antitubercular agent isoniazid than slow acetylators, whereas slow acetylators are more
`prone to isoniazid’s other toxic effects (see Vl|.B.4.d).
`2. The discovery of isoforms and families of CYP45O enzymes has shown that genetic variations
`exist in isoforms that oxidize debrisoquine. Individuals who are poor metabolizers of this
`compound (PM phenotype) also exhibit impaired metabolism of more than 20 other thera-
`peutic agents, including B-blockers, antiarrhythmics, opioicls, and antidepressants. Approxi-
`mately 5%—l0% of whites, 2% of Asians, and 1% of Arabs express the PM phenotype and
`are at risk for adverse drug reactions.
`
`E. Drug dosage
`1. An increase in drug dosage results in increased drug concentrations and can saturate certain
`metabolic enzymes. As drug concentration exceeds 50% saturation for a particular enzyme,
`drug elimination via this path no longer follows solely first-order kinetics, but rather is a
`mix of zero- and first-order kinetics. At 1 00% saturation, metabolism via this enzyme follows
`zero-order kinetics.
`
`2. When the metabolic pathway is saturated (either because of an exceedingly high drug
`level or because the supply of an endogenous Conjugated agent is exhausted), an alternative
`pathway may be pursued. For example, at normal doses, 98% of a dose of acetaminophen
`undergoes conjugation with either glucuronic acid or sulfate; however, at toxic doses,
`conjugation pathways become saturated and acetaminophen undergoes extensive N-hy-
`clroxylation, which can lead to hepatotoxicity.
`F. Nutritional status
`
`1. The levels of some conjugating agents (or endogenous substrates), such as sulfate, g|utathi-
`one, and (rarely) glucuronic acid, are sensitive to body nutrient levels. For example, a low-
`protein diet can lead to a deficiency of certain amino acids, such as glycine. Low-protein
`diets also decrease oxidative drug metabolism capacity.
`
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`Drug Metabolism, Prodrugs, and Pharmacogenetics
`
`405
`
`2. Diets deficient in essential fatty acids (particularly linoleic acid) reduce the metabolism
`of ethyl-morphine and hexobarbital by decreasing synthesis of certain clrug—metabolizing
`enzymes.
`
`3. A deficiency of certain dietary minerals also affects drug metabolism. Calcium, magnesium,
`and zinc deficiencies decrease drug-metabolizing capacity, whereas iron deficiency appears
`to increase it. A copper deficiency leads to variable effects.
`
`4. Deficiencies of vitamins (particularly vitamins A, C, E, and the B group) affect drug-metabo-
`lizing capacity. For example, a vitamin C deficiency can result in a decrease in oxidative
`pathways, whereas a vitamin E deficiency can retard dealkylation and hydroxylation.
`
`G. Age
`
`1. Metabolizing enzyme systems are not fully developed at birth; thus, infants and young
`children need to receive smaller doses of drugs than adults to avoid toxic side effects. This
`is particularly true of drugs that require glucuronide conjugation.
`
`2.
`
`3.
`
`in older children, some drugs may be less active than in adults, particularly if the dosage
`is based on weight. The liver develops faster than the increase in general body weight and,
`thus, represents a greater fraction of total body weight,
`
`in the elderly, metabolizing enzyme systems decline. The lowered level of enzyme activity
`slows the rate ofdrug elimination, causing higher plasma drug levels per dose than in young
`adults.
`
`H. Gender. Metabolic differences between the sexes have been observed for a number of com-
`pounds, suggesting that androgen, estrogen, andfor adrenocorticoid activity might affect the
`activity of certain CYP450 enzyme isozymes.
`
`1. Metabolism of diazepam, prednisolone, caffeine, and acetaminophen is slightly faster in
`women.
`
`2. Oxidative metabolism of propranolol, chlordiazepoxide, lidocaine, and some steroids oc-
`curs faster in men than in women.
`
`I. Circadian rhythms. The nocturnal plasma levels of drugs, such as theophylline and cliazeparn,
`are lower than the diurnal plasma levels.
`
`J. Drug administration route
`
`1. Oral administration. The drug is absorbed from the GI tract and transported to the liver
`through the hepatic portal vein before entering the systemic circulation. Thus, the drug is
`subject to hepatic metabolism before it reaches its site of action. This is an effect known
`as the first-pass effect, or presystemic elimination (Table 175).
`a. The first—pass effect can cause significant clinical problems. Because drugs are metabo-
`lized in the liverfrom their active forms to inactive forms, this effect must be counteracted
`to achieve the desired plasma or tissue drug level.
`I). A common approach is to increase the oral dose, offsetting the loss of drug activity
`from the first—pass effect.
`
`
`Table 17-5. Examples of Drugs That Undergo First~Pass Metabolism
`Acetaminophen
`Fluorouracil
`Oxprenolol
`Albuterol
`lmipramine
`Pentazocine
`Alprenolol
`lsoproterenol
`Progesterone
`Aspirin
`Lidocaine
`Propoxyphene
`Cortisone
`Meperidine
`Propranolol
`Cyclosporin
`Methyltestosterone
`Salbutamol
`Desipramine
`Metoprolol
`Terbutaline
`Dlhydropyridines
`Nortriptyline
`Testosterone
`Estraciiol
`Organic Nitrates
`Verapamil
`
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`406
`
`Chapter 17 ill]
`
`Table 17-6. Examples of Common CYP3A4 Inhibitors and inducers
`Potent Inhibitors
`Moderate Inhibitors
`lnducers
`Amiodarone
`Arnprenavir
`Carbarnazepine
`Atazanavir
`Ciprofloxacin
`Efavirenz
`Clarithromycin
`Diltiazem
`Nevirapine
`lndinavir
`Erythromycin
`Phenytoin
`ltraconazole
`Fluconazole
`Phenobarbital
`Ketoconazole
`Fluvoxamine
`Rifabutin
`Nefazodone
`Grapefruit juice
`Rifapentine
`Nelfinavir
`Norfloxacin
`Rifampin
`Ritonavir
`Verapamil
`St. John’s Wort
`Telithromycin
`Troleandomycin
`Voriconazole
`
`2. Intravenous administration bypasses the first-pass effect because the drug is delivered di-
`rectly to the bloodstream without being metabolized in the liver. Thus, intravenous doses
`of drugs undergoing considerable first-pass effects are much smaller than oral doses.
`3. Sublingual administration and rectal administration also bypass first—pass effects, although
`rectal administration can produce variable effects.
`
`K. Concurrent drug therapy. The co-administration of drugs that are capable of either inhibiting
`or inducing specific CYP450 isozymes can increase or decrease, respectively, the plasma levels
`of other drugs that require these isozymes for normal drug metabolism.
`1. As indicated on Table 17-1, most drugs are metabolized by the following three isozymes:
`CYP2C9, CYP2 D6, and CYP3A4. The potential for drug interactions due to enzyme inhibi-
`tion or induction is therefore greater with these compounds.
`2. Drugs that alter the activity of CYP4S0 isozymes are usually substrates of these same iso-
`zymes. This can be observed by comparing Tables 17-1 and 17-6.
`3. The clinical outcome of these types of drug interactions depends upon three factors:
`a. The potency of the inhibitor or inducer (Table 17-6)
`b. The availability of alternate elimination pathways
`c. The extent to which the higher or lower plasma concentrations of the drug causes
`symptoms andfor undesirable effects.
`
`IV. EXTRAHEPATIC METABOLISM
`
`A. Definition. Extrahepatic metabolism refers to drug biotransformation that takes place in tissues
`other than the liver. The most common sites include the portals of entry (e.g., GI mucosa,
`nasal passages, lungs) and the portals of excretion (e.g., kidneys). However, metabolism can
`occur throughout the body.
`
`B. Metabolism sites
`1. Plasma contains esterases, which are responsible primarily for hydrolysis of esters. Simple
`esters (e.g., procaine, succinylcholine) are rapidly hydrolyzed in the blood. Additionally,
`plasma esterases can activate a variety of ester prodrugs.
`2. Metabolizing enzymes in the intestinal mucosa are especially important for drugs undergo-
`ing microsomal oxidation, glucuronicle conjugation, and sulfate conjugation.
`a. As a lipid—soluble drug passes through the intestinal mucosa during drug absorption, it
`can be metabolized into polar or inactive metabolites before entering the blood. The
`result is comparable to a first-pass effect.
`
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`Drug Metaboiism, Prodrugs, and Pharmacogenetics
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`407
`
`b. The intestinal mu_cosa’s drug—metabolizing capacity compares to that of the liver. How-
`ever, it shows much greater individual variation because of its greater exposure to the
`environment.
`
`3. Intestinal bacterial flora secrete a number of enzymes capable of metabolizing drugs and
`other xenobiotics.
`a. Any factor that modifies the intestinal flora may also modify drug activity. Age, diet,
`disease state, and exposure to environmental chemicals or drugs may all be important.
`(1) Certain diseases, particularly intestinal disease, affect intestinal flora. Ulcerative
`colitis, for example, promotes bacterial growth. Diarrhea reduces the number of
`bacteria.
`(2) Certain environmental chemicals and drugs also act on intestin