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Metabolic Changes of Drugs

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  1. Metabolic Changes of Drugs Books: 1. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry 11th ed. Lippincott, Williams & Wilkins ed. 2. Foye’s Principles of Medicinal Chemistry

  2. Introductory Concepts • Biochemically speaking: Metabolism means Catabolism (breaking down of substances) + Anabolism (building up or synthesis of substances) • But when we speak about drug metabolism, it is only catabolism • That is drug metabolism is the break down of drug molecules • So what is building the drug molecules? We use the word “synthesis”, then • Drugs are synthesized in laboratory and thus is not an endogenous event • Lipid soluble drugs require more metabolisms to become polar, ionizable and easily excretable which involve both phase I and phase II mechanisms.

  3. What Roles are Played by Drug Metabolism? • One of four pharmacokinetic parameters, i.e., absorption, distribution, metabolism and excretion (ADME) • Elimination of Drugs: Metabolism and excretion together are elimination • Excretion physically removes drugs from the body The major excretory organ is the kidney. The kidney is very good at excreting polar and ionized drugs without any major metabolism. The kidney is unable to excrete drugs with high LWPC • In general, by metabolism drugs become more polar, ionizable and thus more water soluble to enhance elimination • It also effect deactivation and thus detoxication or detoxification • Many drugs are metabolically activated (Prodrugs) • Sometimes drugs become more toxic and carcinogenic

  4. Routes that result in the formation of inactive metabolites are often referred to as detoxification. The metabolite may exhibit either a different potency or duration of action or both to the original drug.

  5. Stereochemistry of Drug Metabolism

  6. Sites of Drug Metabolism • Liver: Major site, well organized with all enzyme systems The first-pass effect Following drugs are metabolized extensively by first-pass effect: Isoproterenol, Lidocaine Meperidine, Morphine, Pentazocine, Propoxyphene, Propranolol, Nitroglycerin, Salicylamide • Intestinal Mucosa: The extra-hepatic metabolism, contains CYP3A4 isozyme • Isoproterenol exhibit considerable sulphate conjugation in GI tract • Levodopa, chlorpromazine and diethylstilbestrol are also reportedly metabolized in GI tract • Esterases and lipases present in the intestine may be particularly important carrying out hydrolysis of many ester prodrugs • Bacterial flora present in the intestine and colon reduce many azo and nitro drugs (e.g., sulfasalazine) • Intestinal b-glucuronidase can hydrolyze glucuronide conjugates excreted in the bile, thereby liberating the free drug or its metabolite for possible reabsorption (enterohepatic circulation or recycling)

  7. Enzymes Involved in Drug Metabolism CYP450, Hepatic microsomal flavin containing monooxygenases (MFMO or FMO) Monoamine Oxidase (MAO) and Hydrolases • Cytochrome P450 system: localized in the smooth endoplasmic reticulum. • Cytochrome P450 is a Pigment that, with CO bound to the reduced form, absorbs maximally at 450nm • Cytochromes are hemoproteins (heme-thiolate) that function to pass electrons by reversibly changing the oxidation state of the Fe in heme between the 2+ and 3+ state and serves as an electron acceptor–donor • P450 is not a singular hemoprotein but rather a family of related hemoproteins. Over 1000 have been identified in nature with ~50 functionally active in humans with broad substrate specificity Simplified apoprotein portion Heme portion with activated Oxygen

  8. Cytochrome P450: Naming • Before we had a thorough understanding of this enzyme system, the CYP450 enzymes were named based on their catalytic activity toward a specific substrate, e.g., aminopyrine N-demethylase now known as CYP2E1 • Currently, all P450’s are named by starting with “CYP” (CYtochrome P450, N1, L, N2 - the first number is the family (>40% homology), the letter is the subfamily (> 55% homology), and the second number is the isoform. The majority of drug metabolism is by ~10 isoforms of the CYP1, CYP2 and CYP3 families in humans • Major human forms of P450: Quantitatively, in the liver the percentages of total P450 protein are: CYP3A4 – 28%, CYP2Cx – 20%, CYP1A2 – 12%, CYP2E1 – 6%, CYP2A6 – 4%, CYP2D6 – 4% • By number of drugs metabolized the percentages are: CYP3A4 – 35%, CYP2D6 – 20%, CYP2C8 and CYP2C9 – 17%, CYP2C18 and CYP2C19 - 8% CYP 1A1 and CYP1A2 -10%, CYP2E1 – 4%, CYP2B6 – 3%

  9. Few Important CYP450 Isozymes

  10. Drug Interactions & Metabolism The drug interactions depend upon: the isoform(s) required by the drug in question, the isoforms altered by concomitant therapy, the type of enzyme alteration (induction or inhibition).

  11. General Metabolic Pathways Oxidation • Aromatic moieties • Olefins • Benzylic & allylic C atoms and a-C of C=O and C=N • At aliphatic and alicyclic C • C-Heteroatom system C-N (N-dealkylation, N-oxide formation, N-hydroxylation) C-O (O-dealkylation) C-S (S-dealkylation, S-oxidation, desulfuration) • Oxidation of alcohols and aldehydes • Miscellaneous Hydrolytic Reactions • Esters and amides • Epoxides and arene oxides by epoxide hydrase Phase II - Conjugation Phase I - Functionalization Drug Metabolism Reduction • Aldehydes and ketones • Nitro and azo • Miscellaneous • Glucuronic acid conjugation • Sulfate Conjugation • Glycine and other AA • Glutathion or mercapturic acid • Acetylation • Methylation

  12. Tetrahydrocannabinol (D1-THC) Metabolism The metabolite is polar, ionisable and hydrophilic

  13. Oxidative Reactions

  14. Hydroxylation is the primary reaction mediated by CYP450 • Hydroxylation can be followed by non-CYP450 reactions including conjugation or oxidation to ketones or aldehydes, with aldehydes getting further oxidized to acids • Hydroxylation of the carbon α to heteroatoms often lead to cleavage of the carbon – heteroatom bond; seen especially with N, O and S, results in N–, S– or O–dealkylation. • Must have an available hydrogen on atom that gets hydroxylated, this is important!!!

  15. Epoxide Hydrase OH OH Aromatic Hydroxylation • Mixed function oxidation of arenes to arenolsvia an epoxide intermediate arene oxide • Major route of metabolism for drugs with phenyl ring • Occurs primarily at para position • Substituents attached to aromatic ring influence the hydroxylation • Activated rings (with electron-rich substituents) are more susceptible while deactivated (with electron withdrawing groups, e.g., Cl, N+R3, COOH, SO2NHR) are generally slow or resistant to hydroxylation

  16. Amphetamine Phenytoin p-hydroxyphenytoin Warfarin sodium 17-a-Ethinylestradiol Propranolol Phenylbutazone Atorvastatin

  17. Antihypertensive drug clonidine undergo little aromatic hydroxylation and the uricosuric agent probenecid has not been reported to undergo any aromatic hydroxylation Probenecid Clonidine Preferentially the more electron rich ring is hydroxylated Diazepam Chlorpromazine NIH Shift: Novel Intramolecular Hydride shift named after National Institute of Health where the process was discovered. This is most important detoxification reaction for arene oxides

  18. Oxidation of olefinic bonds (also called alkenes) • The second step may not occur if the epoxide is stable, usually it is more stable than arene oxide • May be spontaneous and result in alkylation of endogenous molecules • Susceptable to enzymatic hydration by epoxide hydrase to form trans-1,2-dihydrodiols (also called 1,2-diols or 1,2-dihydroxy compounds) • Terminal alkenes may form alkylating agents following this pathway Q.Any similarities or dissimilarities with aromatic – NIH Shift, Conjugation with macromolecules?

  19. Tolbutamide Metabolism Tolmetin sodium Benzylic Carbon Hydroxylation • Hydroxylate a carbon attached to a phenol group (aromatic ring) • R1 and R2 can produce steric hindrance as they get larger and more branched • So a methyl group is most likely to hydroxylate • Primary alcohol metabolites are often oxidized further to aldehyde and carboxylic acids and secondary alcohols are converted to ketones by soluble alcohol and aldehyde dehydrogenase Dicarboxylic acid is the major metabolite

  20. Oxidation at Allylic Carbon Atoms

  21. Pentazocine

  22. Hydroxylation at C a to C=O and C=N The benzodiazepines are classic examples with both functionalities The sedative hypnotic glutethimide possesses C a to carbonyl function

  23. Aliphatic hydroxylation • Catalyzes hydroxylation of the ω and ω-1 carbons in aliphatic chains • Generally need three or more unbranched carbons Pentobarbital Metabolism Ibuprofen Metabolism +

  24. Alicyclic (nonaromatic ring) Hydroxylation • Cyclohexyl group is commonly present in many drug molecules • The mixed function oxydase tend to hydroxylate at the 3 or 4 position of the ring • Due to steric factors if position 4 is substituted it is harder to hydroxylate the molecules Acetohexamide Metabolism

  25. Oxidation Involving Carbon-Heteroatom Systems • C-N, C-O and occasionally C-S • Two basic types of biotransformation processes: • Hydroxylation of a-C attached directly to the heteroatom (N,O,S). The resulting intermediate is often unstable and decomposes with the cleavage of the C-X bond: Oxidative N-, O-, and S-dealkylation as well as oxidative deamination reaction fall under this category • Hydroxylation or oxidation of heteroatom (N, S only, e.g., N-hydroxylation, N-oxide formation, sulfoxide and sulfone formation) • Metabolism of some N containing compounds are complicated by the fact that C or N hydroxylated products may undergo secondary reactions to form other, more complex metabolic products (e.g., oxime, nitrone, nitroso, imino)

  26. C-N systems • Aliphatic (1o, 2o,3o,) and alicyclic (2o and 3o) amines; Aromatic and heterocyclic nitrogen compounds; Amides • Enzymes: • CYP mixed-function oxidases: a-C hydroxylation and N-oxidation • Amine oxidases or N-oxidases (non-CYP, NADPH dependent flavoprotein and require O): N-oxidation • 3o Aliphatic and alicyclic amines are metabolized by oxidative N-dealkylation (CYP) • Aliphatic 1o, 2o amines are susceptible to oxidative deamination, N-dealkylation and N-oxidation reactions • Aromatic amines undergoes similar group of reactions as aliphatic amines, i.e., both N-dealkylation and N-oxidation

  27. N-Dealkylation (Deamination) • Deamination and N-dealkylation differ only in the point of reference; If the drug is R1 or R2 then it is a deamination reaction and If the drug is R3 or R4 then it is an N-dealkylation • In general, least sterically hindered carbon (a) will be hydroxylated first, then the next, etc. Thus the more substituent on this C, the slower it proceeds; branching on the adjacent carbon slows it down, i.e. R1, R2 = H is fastest. • Any group containing an a-H may be removed, e.g., allyl, benzyl. Quaternary carbon cannot be removed as contain no a-H • The more substituents placed on the nitrogen the slower it proceeds (steric hindrance) • The larger the substituents are the slower it proceeds (e.g. methyl vs. ethyl). In general, small alkyl groups like Me, Et and i–Pro are rapidly removed; branching on these substituents slows it down even more Imipramine N-Dealkylation

  28. Alicyclic Amines Often Generate Lactams

  29. 3oAmine drugs Tamoxifen Lidocaine Disopyramide Diphenhydramine Chlorpromazine Benzphetamine Brompheniramine Alicyclic Amine drugs Meperidine Morphine Dextromethorphan

  30. 2o & 1o Amines Generally, dealkylation of secondary amines occurs before deamination. The rate of deamination is easily influenced by steric factors both on the a-C and on the N; so it is easier to deaminate a primary amine but much harder for a tertiary amine.

  31. Exceptions: Some 2o and 3o amines can undergo deamination directly without dealkylation.

  32. N-Oxidation Aromatic amines 1° amines 2° amines 3° amines

  33. The attack is on the unbonded electrons so 3o amines can be oxidized • Generally, only occurs if nothing else can happen, so it is a rare reaction • Performed by both amine oxidases and hepatic MFO’s • Good examples would include amines attached to quaternary carbons since they cannot be deaminated Chlorphentermine N-Hydroxylation Hydroxylamine Nitroso Nitro Phentermine Amantadine

  34. Amides C-N bond cleavage viaa-C hydroxylation (formation of carbinolamide) and N-hydroxylation reactions

  35. Oxidation involving C-O System (O-Dealkylation) • Converts an ether to an alcohol plus a ketone or aldehyde • Steric hindrance discussion similar to N-dealkylation Trimethoprim O-Dealkylation

  36. Codeine Phenacetin Indomethacin Metoprolol Prazosin • One exception that appears to be a form of O-dealkylation is the oxidation of ethanol by CYP2E1 • In this case R3 is hydrogen instead of carbon to form the terminal alcohol rather than an ether • The enzyme involved is CYP2E1 and has been historically referred to as the Microsomal Ethanol Oxidizing System (MEOS)

  37. Oxidation involving C-S System • S-Dealkylation • Desulfuration • S-Oxidation Steric hindrance discussion similar to N-dealkylation

  38. Oxidative Dehalogenation • Requires two halogens on carbon • With three there is no hydrogen available to replace • With one, the reaction generally won’t proceed • The intermediate acyl halide is very reactive Q. What is Gray Baby Syndrome?

  39. Hepatic Microsomal Flavin Containing Monooxygenases (MFMO or FMO) • Oxidize S and N functional groups • Mechanism is different but end products are similar to those produced by S and N oxidation by CYP450 • FMO’s do not work on primary amines • FMO’s will not oxidize substrates with more than a single charge • FMO’s will not oxidize polyvalent substrates Cimetidine MFMO S-Oxidation Q. What is the difference with MFO?

  40. Non-Microsomal Oxidation Reactions • Monoamine oxidase (outer membrane of mitochondria, flavin containing enzyme ) • Dehydrogenases (cytoplasm) • Purine oxidation (Xanthene oxidase) Monoamine oxidase • Two MAOs have been identified: MAO–A and MAO–B. Equal amounts are found in the liver, but the brain contains primarily MAO–B; MAO–A is found in the adrenergic nerve endings • MAO–A shows preference for serotonin, catecholamines, and other monoamines with phenolic aromatic rings and MAO–B prefers non–phenolic amines • Metabolizes 1° and 2° amines; N must be attached to α-carbon; both C & N must have at least one replaceable H atom. 2° amines are metabolized by MAO if the substituent is a methyl group • b–Phenylisopropylamines such as amphetamine and ephedrine are not metabolized by MAOs but are potent inhibitors of MAOs

  41. Alcohol dehydrogenase Aldehyde dehydrogenase Metabolizes 1° and 2° alcohols and aldehydes containing at least one “H” attached to a-C; 1° alcohols typically go to the aldehyde then acid; 2° alcohols are converted to ketone, which cannot be further converted to the acid. The aldehyde is converted back to an alcohol by alcohol (keto) reductases (reversible), however, it goes forward as the aldehyde is converted to carboxylic acid; 3° alcohols and phenolic alcohols cannot be oxidized by this enzyme; No “H” attached to adjacent carbon Ethanol Metabolism Purine oxidation Molybdenum Containing

  42. Reductive Reactions • Bioreduction of C=O (aldehyde and keton) generates alcohol (aldehyde → 1o alcohol; ketone → 2o alcohol) • Nitro and azo reductions lead to amino derivatives • Reduction of N-oxides to their corresponding 3o amines and reduction of sulfoxides to sulfides are less frequent • Reductive cleavage of disulfide (-S-S-) linkages and reduction of C=C are minor pathways in drug metabolism • Reductive dehalogenation is a minor reaction primarily differ from oxidative dehalogenation is that the adjacent carbon does not have to have a replaceable hydrogen and generally removes one halogen from a group of two or three

  43. Reduction of Aldehydes & Ketones • C=O moiety, esp. the ketone, is frequently encountered in drugs and additionally, ketones and aldehydes arise from deamination • Ketones tend to be converted to alcohols which can then be glucuronidated. Aldehydes can also be converted to alcohols, but have the additional pathway of oxidation to carboxylic acids • Reduction of ketones often leads to the creation of an asymmetric center and thus two stereoisomeric alcohols are possible • Reduction of a, b –unsaturated ketones found in steroidal drugs results not only in the reduction of the ketone but also of the C=C • Aldo–keto oxidoreductases carry out bioreductions of aldehydes and ketones. Alcohol dehydrogenase is a NAD+ dependent oxidoreductase that oxidizes alcohols but in the presence of NADH or NADPH, the same enzyme can reduce carbonyl compounds to alcohols

  44. Naloxone Daunomycin Naltrexone

  45. Reduction of Nitro & Azo Compounds

  46. R1 and R2 are almost always aromatic • Usually only seen when the NO2 functional group is attached directly to an aromatic ring and are rare • Nitro reduction is carried out by NADPH-dependent microsomal and soluble nitroreductases (hepatic) • NADPH dependent multicomponent hepatic microsomal reductase system reduces the azo • Bacterial reductases in intestine can reduce both nitro and azo Dantrolene Sulfasalazine Clonazepam