the organic chemistry of drug design and drug action chapter 8 drug metabolism

The Organic Chemistry of Drug Design and Drug Action Chapter 8 Drug Metabolism

Foreign organism elicits antibody response Low molecular weight xenobiotics nonspecific enzymes convert them into polar molecules for excretion Enzymatic biotransformations of drugs drug metabolism

Principal site of drug metabolism is the liver; also kidneys, lungs, GI tract take via mouth absorbed through small intestine or stomach bloodstream liver (first metabolized) Drug metabolism by liver enzymes first-pass effect Pathway of Oral Drugs

Avoid first-pass effect by changing the route of administration sublingual route (under the tongue) bypasses liver rectal route (suppository or enema) intravenous (i.v.) injection rapid response, circulation time of 15 seconds - angina (sublingual) - migraine headaches (rectal)

intramuscular (i.m.) injection for large volumes or slow absorption subcutaneous (s.c.) injection through loose connective tissue of s.c. layer of skin pulmonary absorption gaseous or highly volatile drugs topical application Avoid first-pass effect by changing the route of administration (contd) Prodrug approaches are discussed in Chapter 9 - asthma (aerosol)

Drug metabolism is desirable once drug has reached site of action may produce its effect longer than desired or become toxic. Drug metabolism studies are essential for the safety of drugs. Metabolites must be isolated and shown to be nontoxic.

An active metabolite that is less toxic Terfenadine is cardiotoxic, since it binds to the hERG channel Fexofenadine has similar antihistamine activity, but no hERG activity

Synthesis of Radioactive Compounds To increase sensitivity for detection of metabolites, radioactivity is incorporated into the drug candidate. Incorporate a commercial radioactive compound near the end of the synthesis, if possible. Usually the radioactive synthesis is different from that of the unlabeled compound. [ 14 C] preferable to [ 3 H] 3 H has shorter t 1/2 ; isotope effect on C-H cleavage; loss of 3 H as 3 H 2 O if C-H cleavage occurs Only a trace amount of radioactivity is used (maybe 1 in 10 6 molecules); the remainder of the molecules is nonradiolabeled.

Metabolism of erythromycin If the NMe 2 group is labeled with 14 C, the [ 14 C]-CO 2 can be measured.

If the drug is a natural product, a biosynthetic approach to radioactive incorporation is best SCHEME 8.1 Biosynthesis of penicillins

If the drug is not a natural product, a chemical synthesis is needed. [ 14 C] acetic anhydride could be used here SCHEME 8.2 Chemical synthesis of linezolid

The radioactive drug is used in metabolism and bioavailability studies in rats, mice, or guinea pigs, then in dogs and/or monkeys. If >95% of the radioactivity is found in urine and feces, and is nontoxic, it can be administered to humans. Phase I clinical trials on healthy volunteers radiolabeled drug administered to humans for human metabolism studies.

Advances that Made Metabolism Studies Less Difficult More commercially-available radioactive compounds High performance liquid chromatography (HPLC); new column packings; capillary GC; capillary electrophoresis New mass spectrometric methods tandem mass spectrometry/mass spectrometry; GC/mass spectrometry; *HPLC/electrospray mass spectrometry New nuclear magnetic resonance (NMR) techniques *HPLC/NMR *HPLC/NMR/MS

Principal Steps in Drug Metabolism Studies 1.Isolation (often, this step can be omitted) extractions, ion exchange 2.Separations HPLC, GC 3.Identification mass spectrometry (MS), NMR 4.Quantification radioactive labeling, GC, HPLC LC/MS/MS is a rapid method in which a sample is injected into the HPLC, then each peak is run into an electrospray ionization MS for parent ion data, then the parent ion is run into a second MS for fragmentation data.

Pathways for Drug Deactivation and Elimination Rate and pathway of drug metabolism are affected by species, strain, sex, age, hormones, pregnancy, and liver diseases. Drug metabolism is stereoselective, if not stereospecific. Generally, enantiomers act as two different xenobiotics different metabolites and pharmacokinetics. Sometimes the inactive enantiomer produces toxic metabolites or may inhibit metabolism of active isomer. Metabolism of enantiomers may depend on the route of administration. For example, the antiarrhythmia drug verapamil is 16 times more potent when administered i.v. than orally.

As the lipophilicity increases, metabolism increases; increased lipophilicity leads to better substrate activity with metabolizing enzymes. FIGURE 8.1 Effects of lipophilicity on direct renal clearance and on metabolism

Verapamil is 16 times more active IV than orally The more active (-) isomer is metabolized faster than the (+) isomer by the liver

One enantiomer can be metabolized to the other. (Advil) Inactive (R)-isomer is metabolized to active (S)-isomer No need to use a single enantiomer

Drug metabolism reactions two categories Phase I transformations introduce or unmask a functional group, e.g., by oxygenation or hydrolysis Phase II transformations generate highly polar derivatives (called conjugates) for excretion

Phase I Transformations Oxidative Reactions Cytochrome P450 family of heme enzymes that catalyzes the same reaction on different substrates (isozymes) Late 1940s, early 1950s Metabolism of 4-dimethylaminoazobenzene shown to require O 2 and a reducing system (NADPH). Called a mixed function oxidase. One atom of O from O 2 is incorporated into product; a heme protein is involved.

Drug-Drug Interactions Changes in the pharmacokinetics and metabolism of drugs when multiple drugs are taken together. One drug may inhibit a cytochrome P450, blocking metabolism of another drug. One drug may induce a cytochrome P450, which increases metabolism of other drugs.

Hyperforin is found in St. Johns Wort Active constituent of St. Johns wort (hyperforin, 8.11) activates the pregnane X receptor, which regulates P450 3A4 transcription, resulting in more active drug metabolism

Heme-dependent Mixed Function Oxidase Scheme 4.35 Oxidizing agent Reducing agent Activated coenzyme

Reactions Catalyzed by Cytochrome P450

Site of Reactions Catalyzed by P450 Part of molecule undergoing reaction is determined by: 1.topography of the active site of the isozyme 2.degree of steric hindrance of the heme iron-oxo species to the site of reaction 3.ease of H atom abstraction or electron transfer from the compound

CYP450 activity is variable in the population CYP450 is found in liver, kidney and lungs. There are a number of different P450 families, which differ in their substrate and reaction specificity. 57 human genes for P450 have been indentified. Individuals also vary in the properties of their P450s. CYP450 2C9 and 2D6 are responsible for metabolism of about half of all drugs. Variations in P450s are racially and ethnically distributed. Pharmacogenomicshow the genetic characteristics of a person influences their response to drugs.

Individual variation in CYP450 2C9 CYP450 2C9 metabolizes phenytoin, S-warfarin, tolbutamide, losartan, and many nonsteroidal antiinflammatory agents (NSAIDs). At least 33 alleles of CYP450 2C9 have been discovered. Most of the mutant alleles of CYP450 2C9 have low or no enzymatic activity.

CYP450 2C9 and tolbutamide metabolism Tolbutamide is a sulfonylurea antidiabetes drug. CYP450 2D9 hydroxylates the aromatic methyl to give a much lower activity metabolite. Individuals with mutant CYP450 2C9 alleles have higher concentrations of tolbutamide in the blood, longer duration of action, and lower blood glucose, so they are more likely to get hypoglycemia.

CYP450 2C9 and warfarin metabolism Warfarin is an anticoagulant drug which inhibits vitamin K 2,3-epoxide reductase. (S)-Warfarin is hydroxylated at C-6 and C-7 by CYP450 2C9 to give inactive metabolites. Mutant alleles of CYP450 2C9 have less activity for hydroxylation of warfarin, so patients with mutant alleles need to have lower doses. The therapeutic index for warfarin is small even for wild-type patients.

Individual variation in CYP450 2D6 P450 2D6 metabolizes opiates, antiarrhytmics, tamoxifen and -blockers, among others. More than 60 alleles of 2D6 have been discovered. Some of the alleles of 2D6 have low or no enzymatic activity (PM). Some of the alleles of 2D6 have intermediate activity (IM). Some of the alleles of 2D6 have somewhat higher activity (EM). Some of the alleles of 2D6 have much higher activity than wild-type (UM).

CYP450 2D6 and opiate metabolism Codeine is O-demethylated to morphine, the active metabolite in analgesia. PMs cant convert codeine to morphine, so dont get analgesia. UMs convert codeine to morphine very rapidly, so may experience toxicity. Infants have been poisoned by breast milk from UM mothers taking codeine.

CYP450 2D6 and tamoxifen metabolism Tamixofen is an antiestrogen used to treat breast cancer. The metabolite, 4-hydroxytamoxifen, binds about 100-fold more strongly to estrogen receptors. 2D6 PMs respond poorly to tamoxifen treatment.

Reactions of Flavin Monooxygenase Table 8.2 Flavin monooxygenase is often more stereoselective than CyP450 CyP450 FMO

Flavin Monooxygenase (another mixed function oxidase) Scheme 4.34 X is N or S Nucleophiles with anionic groups are not substrates

Aromatic Hydroxylation Jerina, Daly and Witkop 1968 National Institutes of Health (NIH) arene oxide isolated Intermediate in aromatic hydroxylation SCHEME 8.3 Cytochrome P450 oxidation of naphthalene

Mechanism for Arene Oxide Formation and Aromatic Hydroxylation (favored over a) SCHEME 8.4 Additionrearrangement mechanism for arene oxide formation

Reactions of Arene Oxides toxic effects SCHEME 8.5 Possible fates of arene oxides

Rearrangement of Arene Oxide to Arenol Called the NIH shift SCHEME 8.6 Rearrangement of arene oxides to arenols (NIH shift)

Competing with the NIH Shift deprotonation The more stabilized the carbocation intermediate, the less favored for hydride shift - more deprotonation. SCHEME 8.7 Competing pathway for NIH shift

Deuteration can reduce metabolism Deuterated linezolid has t 1/2 = 6.3 h, compared to 4.5 h

NIH Shift with Groups Other than H p-chloroamphetamine Oxidation of a halogen-substituted aromatic ring is quite rare. SCHEME 8.8 NIH shift of chloride ion

A common approach to slow down or block aromatic hydroxylation is to substitute the phenyl ring with a para-fluorine or para-chlorine (deactivates the ring). The half-life for the anti-inflammatory drug diclofenac (8.22) is 1 h; for fenclofenac (8.23) is >20 h.

NIH Shift of a Nitro Group Scheme 8.9 antiprotozoal

This reaction is electrophilic aromatic substitution Favors electron-donating substituents No aromatic hydroxylation if strongly electron-withdrawing substituents e - withdrawing uricosuric agent

For drugs with 2 aromatic rings, the more e - -rich one usually is hydroxylated. hydroxylation here e - withdrawing - antipsychotic

Species Specificity Major hydroxylation metabolites in dogs Maybe a different isozyme pro-R - antiepilepsy pro-S in humans

Mechanism of Epoxide Hydrolase Hydration of Arene Oxide trans-diol anti- attack SCHEME 8.10 Metabolic formation and oxidation of catechols

Glutathione S-transferase Reaction with Arene Oxide SCHEME 8.11 Formation of glutathione adducts from naphthalene oxides

Toxicity from Arene Oxides benzo[a]pyrene alkylation of DNA and RNA Relationship between soot and cancer noted in 1775 - chimney sweeps frequently developed skin cancer SCHEME 8.12 Deoxyribonucleic acid adduct with benzo[a]pyrene metabolite

Alkene Epoxidation Also an anticonvulsant anticonvulsant SCHEME 8.13 Metabolism of carbamazepine

Toxic Product of Alkene Oxygenation aflatoxin B 1 DNA adduct SCHEME 8.14 Metabolic reactions of aflatoxin B 1

Oxidation of Carbons Adjacent to sp 2 Centers Oxygenation next to aromatic sp 2 carbon antidepressant

Hydroxylation stereochemistry at C-1 depends on stereochemistry at C-2 in metoprolol. antihypertensive Stereochemistry at C-2 will affect how the molecule binds in P450, which determines which H is closest to the heme iron-oxo species.

Allylic Hydroxylation antiarrhythmic Oxidation gives 7.38 (R = OH)

Allylic hydroxylation of THC

Oxidation Next to a Carbonyl Group Enantiomer difference in metabolism hydroxylation here for (+)-isomer hydroxylation here for (-)-isomer sedative/hypnotic

Oxidation at Aliphatic and Alicyclic Carbons anticonvulsant Both positions are hydroxylated

Perhexiline is hydroxylated

Hydroxylation beta to a Carbonyl Group SCHEME 8.15 C-demethylation of a flutamide metabolite

Oxidations of Carbon-Nitrogen Systems

Oxidative Deamination Cleavage of NH 3 from 1 amines SCHEME 8.16 Oxidative deamination of primary amines

Oxidative Deamination of amphetamine

SCHEME 8.17 N-Oxidation pathways of amphetamine N-Oxidation-Hydroxylation of Nitrogen Basic amines (pK a 8-11) are oxidized by flavoenzymes. Nonbasic compounds, such as amides, are oxidized by P450. Compounds of intermediate basicity, such as aromatic amides, are oxidized by both.

Alternative Pathway to Ketone SCHEME 8.18 Amphetamine imine formation via the carbinolamine

Metabolism of 2 Amines and Amides

Oxidative N-Dealkylation SCHEME 8.19 Oxidative N-dealkylation of secondary amines

Oxidation here ab SCHEME 8.20 Oxidative metabolism of propranolol

N-Oxidation of 2 Amines anorectic Further oxidation occurs SCHEME 8.21 N-Oxidation of fenfluramine

Oxidation of 3 Amines and Amides No oxidative deamination

Oxidative N-Dealkylation Rate of oxidative N-dealkylation of 3 amines > oxidative N-dealkylation of 2 amines > oxidative deamination of 1 amines antihypertensive drug Rate of metabolism R = NMe 2 > NHMe > NH 2 antidepressant drug

Enantioselective Oxidative N-Dealkylation N-Demethylation of (+)-isomer is slower than that of (-)-isomer narcotic analgesic

(S)-(+)-deprenyl (S)-(+)-methamphetamine (S)-(+)-amphetamine weak MAO B inhibitor undesirable CNS stimulant (R)-(-)-deprenyl (R)-(-)-methamphetamine (R)-(-)-amphetamine potent MAO B inhibitor weak CNS stimulant Therefore only the (R)-(-)-isomer is used SCHEME 8.22 Metabolism of selegiline (deprenyl)

Rasagiline avoids the stimulation problem with Seligiline

Alicyclic 3 Amine Oxidation SCHEME 8.23 Oxidative metabolism of nicotine leading to CN bond cleavage.

Evidence for Iminium Ion Intermediates local anesthetic isolated SCHEME 8.24 Metabolism of lidocaine

N-Oxidation of 3 Amines N-Oxidation antihypertensive

Cyproheptadine forms the N- oxide in dogs

N-Oxidation of 3 Aromatic Amines Two enzymes systems: P450 and flavin monooxygenase P450 catalyzed N-oxidation N-Oxidation by P450 occurs only if there are no -hydrogens available or if the iminium radical is stabilized by electron donation. SCHEME 8.25 Mechanism of cytochrome P450-catalyzed N-oxidation of tertiary aromatic amines

Flavin Monooxygenase-Catalyzed N-Oxidation of Aromatic Amines Primary aromatic amines are generally not substrates for flavin monooxygenase; 2 and 3 aromatic amines are good substrates. SCHEME 8.26 Possible mechanism for N-oxidation of primary arylamines

Two Pathways for N-Demethylation of 3 Aromatic Amines SCHEME 8.27 Two pathways to N-demethylation of tertiary aromatic amines

Evidence to Support Carbinolamine Formation R = OH isolated

Mechanism of Carbinolamine Formation Based on low intrinsic isotope effects by P450, direct H abstraction mechanism was excluded. SCHEME 8.28 Mechanism of carbinolamine formation during oxidation of tertiary aromatic amines

N-Oxidation of Aromatic Amines (1 and 2 ) Generation of reactive electrophiles acetylation or sulfation SCHEME 8.29 Metabolic activation of primary and secondary aromatic amines

Cytotoxicity of N-Hydroxylated Amides Mechanism-based inactivator if 8.78 does not escape the enzyme prior to nucleophilic attack SCHEME 8.30 Arylhydroxamic acid N,O-acyltransferase-catalyzed activation of N-hydroxy-2-acetylaminoarenes

Amide N-Demethylation sedative

N-Oxidation of 1 and 2 Aromatic Amides Generation of electrophiles 2-acetylaminofluorene (R = H) carcinogenic agent

SCHEME 8.31 Initial proposals for bioactivation of acetaminophen Toxicity of Acetaminophen Two possible mechanisms for generation of reactive electrophile 8.80

Another possible mechanism for Acetaminophen Hepatotoxicity Ethanol induces a P450 isozyme that generates the radical; alcoholics have a higher incidence of acetaminophen hepatotoxicity. SCHEME 8.32 Bioactivation of acetaminophen via a radical intermediate

Prostaglandin H synthase is in high concentrations in kidneys. Prostaglandin H synthase contains heme just like P450 and catalyzes similar reactions Acetaminophen also causes renal damage, but little P450 is in the kidneys. SCHEME 8.33 Proposed bioactivation of acetaminophen by prostaglandin H synthase

Oxidations of Carbon-Oxygen Systems Oxidative O-Dealkylation Same mechanism as oxidative N-dealkylation O-Demethylation is rapid; as increase alkyl chain length, O-dealkylation gets faster up to propoxyl, then rate decreases. Cyclopropyl gives ethers with longer plasma half lives.

Indomethacin is demethylated

Oxidative O-Dealkylation of codeine analgesic O-Demethylation by Cyp450 2D6 is rapid

Regioselective O-Demethylation In dogs O-demethylation only here blood pressure maintenance

Oxidation on the Carbon Next to a Lactone Oxygen SCHEME 8.34 Metabolic hydroxylation of rofecoxib

Oxidations of Carbon-Sulfur Systems Three principal biotransformations: Oxidative S-dealkylation, desulfuration, and S-oxidation Oxidative S-dealkylation sedative Dealkylation occurs here

Desulfuration (C=S C=O) anesthetic sedative

S-Oxidation Occurs with P450 and flavin monooxygenase Flavin monooxygenase gives sulfoxides only P450 gives both S-dealkylation and sulfoxides SCHEME 8.35 Cytochrome P450-catalyzed oxidation of sulfides

antihelmintic agent Gives both S-dealkylation and S-oxidation metabolites

Thioridazine is oxidized on both sulfurs

Thiophenes are converted to thiophene S-oxides, which are electrophilic and can bind to liver proteins. added in vitro to mimic a liver protein cysteine residue SCHEME 8.36 S-Oxidation of tienilic acid

Oxidation of Sulfoxide to Sulfone Oxisuran, an immunosupressive drug, is oxidized to the sulfone

Other Oxidative Reactions Oxidative Dehalogenation volatile anesthetic SCHEME 8.37 Oxidative dehalogenation of halothane

Oxidative Aromatization

Oxidation products of morphine

Oxidation of Alcohols to Aldehydes and Aldehydes to Carboxylic Acids Scheme 8.38 Oxidation of an aldehyde to a carboxylic acid is generally faster than reduction of an aldehyde to an alcohol. Cytochrome P450 also oxidizes alcohols to aldehydes and aldehydes to carboxylic acids.

Oxidation of an Alcohol to a Carboxylic Acid by NAD + Enzymes anti-AIDS drug

Oxidation of an Alcohol to a Carboxylic Acid by a P450 Isozyme The metabolite is 10 times more potent an antagonist of the angiotensin II receptor than losartan. antihypertensive drug

Reductive Reactions

Carbonyl Reduction Typically aldo-keto reductases that require NADPH or NADH and 7-hydroxyl) as the major metabolites. Administration of racemates can affect the metabolism of each enantiomer. When the racemic mixture was administered, the R-isomer gave aromatic hydroxylation (both 6- Reduced here Hydroxylated here (R)-isomer: (R,S) alcohol (S)-isomer: R=OH + 4:1 (S,S) : (S,R) alcohols

Species Variation in Stereochemistry opioid antagonist used for addiction rehabilitation 6 -alcohol (7.102, R 1 = OH, R 2 = H) in chickens 6 -alcohol (7.102, R 1 = H, R 2 = OH) in rabbits and humans

, -Unsaturated Ketone Double Bonds Reduced The double bond of norgestrel (7.94, R 3 = Et) and norethindrone (7.94, R 3 = Me) is reduced; norgestrel gives 3 -alcohol (R 1 = H, R 2 = OH) but norethindrone gives 3 -alcohol (R 1 = OH, R 2 = H). Double bond reduced

Nitro Reduction SCHEME 8.39 Nitro group reduction

Nitro Reduction Often the amine metabolite is not observed because it is easily air oxidized back to the nitro compound, for example, the anti-parasitic agent niridazole is reduced to the hydroxylamine, but is reoxidized to niridazole, and clonazepam is reduced to the unstable amine.

Nitro reduction with ring opening SCHEME 8.40 Reductive metabolism of nitrofurazone

Azo Reduction SCHEME 8.41 Azo group reduction

Azo Reduction Reduction carried out by intestinal bacteria. SCHEME 8.42 Reductive metabolism of sulfasalazine

Reduction of Azido to Amino Anti-AIDS

3 Amine Oxide Reduction imipramine N-oxide Reduced in the presence of O 2 to the amine

Reductive Dehalogenation Cytochrome P450 in the absence of O 2 May be the cause for Halothane hepatitis SCHEME 8.43 Reductive dehalogenation of halothane

Carboxylation Reactions Metabolized to 8.124, R = COOH

Hydrolytic Reactions (nonspecific esterases and amidases in plasma, liver, kidney, and intestines) Electron-withdrawing groups accelerate hydrolysis. Conjugation with carbonyls decelerates hydrolysis. Steric hindrance decelerates hydrolysis. Hydrolyzed by all human tissues

Selectivity for Aliphatic vs. Aromatic Esters Some esterases catalyze the hydrolysis of aliphatic esters and others aromatic esters. In vivo hydrolysis Hydrolysis by liver enzymes in vitro

Amide vs. Ester Hydrolysis Hydrolysis of procaine >> procainamide Generally amides are more slowly hydrolyzed than esters.

Amide vs. Ester Hydrolysis No amide hydrolysis Ester hydrolysis only

Some amides are hydrolyzed at rates comparable to that of esters (maybe because of electron- withdrawing groups).

Hydrolysis of phenacetin produces a toxic amine

Amide Hydrolysis - Enantiomer Toxicity Both enantiomers are anesthetics (R)-isomer causes methemoglobinemia (S)-isomer not hydrolyzed

Stereospecific metabolism of phensuximide, an anticonvulsant

Enantiomer-Selective Hydrolysis The (R)-(-)-ester is hydrolyzed in the liver, but the (S)-(+)-ester is hydrolyzed in the brain.

Differential Enantiomeric Metabolism SCHEME 8.44 Competitive metabolism of R- and S-etomidate (R)-enantiomer (S)-enantiomer

Phase II Transformations Conjugation Reactions Attachment of small polar endogenous molecules to drugs or (more often) to metabolites of phase I enzymes Further deactivates drugs and produces water- soluble metabolites readily excreted Conjugation reactions take place with hydroxyl, carboxyl, amino, heterocyclic N, and thiol groups; if not present, a phase I reaction introduces it Many drugs are excreted without any modification at all.

Mammalian Phase II Transformations Table 8.7

Glucuronidation Biosynthesis and Reactions of UDP-glucuronic Acid SCHEME 8.45 Biosynthesis and reactions of UDP glucuronic acid

Classes of Compounds Forming Glucuronides

Diseases (inborn errors of metabolism) associated with defective glucuronidation Crigler-Najjar syndrome and Gilberts disease deficiency of UDP-glucuronosyltransferase adverse effects caused by accumulation of drugs inability of neonates to conjugate the antibacterial chloramphenicol (8.142) - gray baby syndrome)

Species Specificity, Regioselectivity, and Stereoselectivity Antibacterial drug sulfadimethoxine is glucuronidated in humans (at arrow) but not in rats, guinea pigs, or rabbits. Sulfadimethoxine

Two different glucuronides are formed here The R,R-(-)-isomer is conjugated with higher affinity, but lower velocity than is the S,S-(+)- isomer.

The two hydroxylated isomers of nortriptyline metabolite 8.144 (R = OH) are glucuronidated stereospecifically. Liver and kidney glucuronosyltransferases convert only the E-(+)- isomer and the intestinal enzyme converts only the (E)-(-)- isomer.

Human UGTs 40-70% of drugs are glucuronidated in humans. Twenty-two UGTs have been identified.

Polymorphisms of UGT1A1

Polymorphisms of UGT1A3

UGT alleles can lead to severe side effects

Sulfate Conjugation Occurs less often than glucuronidation (limited availability of SO 4 = ). Main substrates are phenols, but also aliphatic OH, amines, and thiols (much less).

Glucuronidation and sulfation can occur on the same substrates, but the K m for sulfation is usually lower, so it predominates. bronchodilator sulfation here (phenolic OH instead of aliphatic OH)

Hepatotoxicity and Carcinogenicity by Sulfation SCHEME 8.47 Bioactivation of phenacetin

Amino Acid Conjugation Glycine conjugates are most common in animals. L-Glutamine conjugates are most common in primates (insignificant in nonprimates). SCHEME 8.48 Amino acid conjugation

Metabolism of Brompheniramine (antihistamine) SCHEME 8.49 Metabolism of brompheniramine

Metabolism of diphenhydramine (Benadryl) The pathway is the same as bromopheniramine, except that it is conjugated with glutamine

Glutathione Conjugation Glutathione GSH Found in all mammalian tissues (5-10 mM in liver and kidneys) Scavenger of harmful electrophiles

Glutathione Conjugation SCHEME 8.50 Examples of glutathione conjugation

Further Metabolism of GSH Conjugates Metabolism of glutathione conjugates to N-acetyl- L-cysteine conjugates Referred to as phase III metabolism SCHEME 8.51 Metabolism of glutathione conjugates to mercapturic acid conjugates

Water Conjugation Epoxide hydrolase reactions; such as hydrolysis of arene oxides, as discussed earlier.

Acetyl Conjugation Important for xenobiotics with primary NH 2 Converts ionized amine (RNH 3 ) to uncharged amide + Metabolites are less water soluble; possibly serves the function of deactivating the drug. Occurs widely in animals Extent of N-acetylation in humans is a genetically determined characteristic - called acetylation polymorphism. Egyptians are slow acetylators - toxic buildup of drugs but longer drug effectiveness. East Asians and Canadian Eskimos are fast acetylators - inadequate response.

Acetylation of Amines Makes less polar: RNH 3 + SCHEME 8.52 N-Acetylation of amines

Examples of Drugs Exhibiting Acetylation Polymorphism Antibacterial Antituberculosis Treatment of leprosy

Cilastatin is acetylated. It is administered with Imipenem

Fatty Acid and Cholesterol Conjugation Fatty acid metabolites of 8.177 and 8.178 deposit in liver, spleen, adipose tissue, and bone marrow.

Cholesterol esters can be formed Development of the hypolipidemic drug 8.180 had to be stopped because cholesterol esters deposited in the liver.

Methylation - relatively minor in drug metabolism Generally occurs when the compound has a structural similarity to normal endogenous substrates of the methyltransferase. SCHEME 8.53 Methylation of xenobiotics

Methylated here regiospecifically bronchodilator Methylation by catechol O- methyltransferase requires a catechol (an aromatic 1,2- dihydroxy) substrate. An aromatic 1,3-dihydroxy compound (8.185) does not get methylated.

Phenolic hydroxyls also can get methylated Methylation here (minor)

N-Methylation also occurs to a minor extent. Oxyprenolol is N-dealkylated to 8.187, R = H, which is methylated to 8.187, R = CH 3. antihypertensive

Captopril and propylthiouracil are S-methylated. S-Methylation

Reactive metabolites Atorvastatin and lumiracoxib can form an electrophilic quinone imine.

Hard and Soft Drugs Sometimes a drug is not metabolized rapidly enough (long plasma half life). The plasma half life for an analog (8.196) of the antiarthritis drug celecoxib (8.195) in dogs is about a month! To shorten the plasma half life the para-chloro was changed to para-methyl because a carbon next to an aromatic group is known to undergo P450 oxygenation. plasma t 1/2 9 hplasma t 1/2 680 h

Compounds (like 8.196) that are difficult to metabolize are termed hard drugs. Those that are easily metabolized (like 8.195) are soft drugs (also called antedrugs). Soft drugs are designed to have a predictable and controllable metabolism to nontoxic and inactive products after they have achieved their pharmacological effect.

8.197 is a soft analogue of 8.198, an antifungal

Retro Approach Related to Soft Drugs Identify a biologically inactive metabolite, then modify to an active drug in such a way that this modification is known to be reversed to the inactive metabolite. The anti-inflammatory agent loteprednol etabonate (8.199) was designed based on the known inactive steroid 8.201 [an analog of the anti- inflammatory drug prednisolone (8.200)]. Compound 8.199 is metabolized by esterases to 8.201 after it elicits its anti- inflammatory effect.

the organic chemistry of drug design and drug action chapter 8 drug metabolism

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