Metabolism 1


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Metabolism 1

  1. 1. So far, 74 CYP gene families havebeen described, of which three mainones (CYP1, CYP2, CYP3) areinvolved in drug metabolism inhuman liver. CYP1A2 is one of themain enzyme.(Cytochrome P450 is called ‘superfamily’)
  2. 2. Drug oxidation by the monooxygenase P450system requires drug , P450 enzymes, and inaddition molecular O2 , NADPH and aflavoprotein (NADPH-P450 reductase)
  3. 3. Examples of common drugs that are substrate for P450 isoenzymesIsoenzyme P450 DrugCYP1A1 TheophylineCYP1A2 Caffeine, paracetamolCYP2A6 MethoxyfluraneCYP2 TaxolCYP2C9 Ibuprofen, phenytoin, tolbutamide, warfarin
  4. 4. Cont’d…….CYP2C19 OmeprazoleCYP2D6 Clozepine, codeineCYP2E1 Alcohol, halothaneCYP3A4/ Losartan, nifedipine, terfenadine
  5. 5. P450 and biological variationWithin the human populations there are majorsources of interindividual variation in P450enzymes that are of great importance intherapeutics.These include genetic polymorphisms:For example, one variant of the gene CYP2D6leads to poor or extensive hydroxylation ofdebrisoquine, (an antihypertensive drug).
  6. 6. Cont’d…..Environmental factors: enzymes inducersand inhibitors are present in the diet andenvironment. For example, grapefruit andSt John’s wort inhibit drug metabolism:cardiac dysrythmias.Cigarette smoke induce P450 enzymes
  7. 7. Other enzymes involved Amine oxidase Epoxide hydratase Glucuronyl transferase Esterases and Amidases Alcohol and aldehyde dehydrogenases Sulfotransferases Acetyl transferases Glutathione-s-transferases Methyl transferases Monoamine oxidase
  8. 8. Induction of microsomal enzyme activity Many drugs and chemicals1. Anticonvulsants including phenobarbitone, rifampicin, glucocorticoids induce CYP3A isoenzymes2. Phenobarbitone also induce CYP2B1 and rifampicin also induce CYP2D63. Isoniazid and chronic alcohol consumption induce CYP2E1
  9. 9. 4. Benzopyrine found in cigarette smoke and industrial pollutants induce CYP1A isoenzymes5. Others: DDT(dichloro diphenyl trichloroethane), phenylbutazone, griseofulvin etc.
  10. 10. Inhibition of the microsomal enzyme activity Allopurinol Amiodarone Chloramphenicol Cimetidine Ciprofloxacine Diltiazem Metronidazole Ketokonazole Omeprazole MAO inhibitors Quinidine Sulfonamides
  11. 11. Phase I reactions or non-synthetic reactionHere metabolites are active or inactive Alter chemical reactivity Increase aqueous polarityPhase I reaction consist of-a) Oxidationb) Reductionc) Hydrolysis
  12. 12. In the phase I reaction, it may result in inactivation,change in the activity or inactivation of the parent drugs.In this phase, introducing the drug molecule to polargroup such as -OH, -COOH, -NH2, and –SH. a) OxidationThis reaction involves addition of oxygen/negativelycharged radical or removal of hydrogen /positivelycharged radicalTwo types- 1. Microsomal oxidation 2. Non- microsomaloxidation
  13. 13. a) OxidationThis reaction involves addition ofoxygen/negatively charged radical or removal ofhydrogen /positively charged radicalTwo types- 1. Microsomal oxidation 2. Non-microsomal oxidation
  14. 14. Microsomal oxidation1. Aromatic hydroxylation2. Aliphatic hydroxylation3. N-, O-, or S-dealkylation4. Epoxidation5. Desulfuration6. Deamination7. Sulfoxidation8. N—oxidation9. N- hydroxylation10. Dehalogenation
  15. 15. 1. Aromatic hydroxylation- Acitanilide ----------- p-hydroxyacetanilide (paracetamol or acetaminophen)2. Aliphatic hydroxylation Phenobarbitone --------- phenobarbitone alcohol3. Dealkylation: N-dealkylation- ex- diazepam -------desmethyldiazepam, here N- methyl group can be removed oxidatively
  16. 16. 4. O-deakylation- ex- phenacetin ----- paracetamol ( active metabolites)5. Epoxidation- ex- Vitamin k -------- vitamin k epoxide benzene -------- benzene epoxide6. Desulfuration- ex- Melathion -------Parathion ( more toxic than parent drug)7. Deamination- ex- Amphetamine ------- phenylacetone ( inactive )
  17. 17. b) ReductionDrugs those contain- disulphide (s:s), azo (n:n),or nitro (no2)Azo-ex- Prontosil dye ---------- > SulfanilamideNitro-ex- chloramphenicol --------- > arylamine
  18. 18. c) HydrolysisEx- Acetylcholine -------- choline + acetate Procaine ------------- > p-aminobenzoic acid
  19. 19. Phase II or synthetic or conjugation reactionSix types of phase II reactions.It occur when a drug or Phase I metabolites contains--OH, -COOH, -NH2 , -SH group (Aim: readily excreted more water soluble polar metabolites)Conjugating agents are- Glucuronic acid, Glycine, cysteine, methionine (for methylation), sulfate, acetyl (for acetylation)
  20. 20. Species variation in conjugation reaction candepend on occurrence of the conjugating agent,ability of the body to form the necessarynucleotide or amount of transferring enzymes.Certain conjugation reaction are either defective or absent in particular species.
  21. 21. Cont’d…..Ex.- The cat synthesizes glucuronideconjugation at a slower rate, as this species isdeficient in the transferring enzyme glucuronyltransferaseThe dog and fox are unable to acetylatearomatic amino groups
  22. 22. Glucuronide conjugationDrugs and some endogenous substances,steroid, thyroxine, bilirubin.First of all, glucuronic acid should be activated.The activated form of glucuronic acid is thenucleotide- uridinine diphosphate glucuronic acid(UDPGA)The drugs and endogenous substances that areexcreted largely as glucuronides include-
  23. 23. The drugs and endogenous substances that areexcreted largely as glucuronides include-Drugs:MorphineSalicylatesAcetaminophenChloramphenicolPhase I metabolites ofdiazepam (oxazepam),phenylbutazone (oxyphebylbutazone)
  24. 24. Endogenous substancesSteroidBilirubinThyroxine
  25. 25. Requirement for the formation of glucuronide-UDPGA, drug or its metabolites and glucuronyltransferaseWhy more water soluble?Because, large hydrophilic carbohydrate moietyand more highly ionized at physiological pHvalues