1. DRUG METABOLISM

3. Converting lipophilic to water soluble compounds Xenobiotic Reactive intermediate Conjugate Phase I - Activation Phase II - Conjugation Excretion Lipophilic (non-polar) Water soluble (polar)

4. ORGAN SITES OF DRUG METABOLISM

6. CELLULAR SITES OF DRUG METABOLISM

8. Drug metabolising enzymes

10. Hepatic microsomal enzymes (oxidation, conjugation) Extrahepatic microsomal enzymes (oxidation, conjugation) Hepatic non-microsomal enzymes (acetylation, sulfation,GSH, alcohol/aldehyde dehydrogenase, hydrolysis, ox/red) Drug Metabolism

12. PHASES OF DRUG METABOLISM

13. Phase I Metabolism R R OH R R COOH R R SH R R NH 2 Polar groups are exposed on or introduced to a molecule

14. Phase I Reactions OXIDATION REDUCTION HYDROLYSIS

17. 2.Oxidation of olefins(C=C bond) Carbamazepine Carbamazepine-10, 11-epoxide Trans-10,11-dihydroxy carbamazepine H 2 O H 2 O Epoxide hydrase

18. 3.Oxidation of Benzylic Carbon Atom Tolbutamide Primary Carbinol Corresponding aldehyde Corresponding Carboxylic acid 2 OH

19. 4.Oxidation of Allylic Carbon Atoms Hexobarbital 3-hydroxy Hexobarbital Allylic Carbon Atom

20. 5.Oxidation of Carbon Atoms Alpha to Carbonyls and imines OH Diazepam 3-Hydroxy diazepam

21. 6.Oxidation of Aliphatic Carbon Atoms 5-Hydroxy Valproic Acid(minor product) 4-Hydroxy Valproic Acid(major product) OH HO ω -Oxidation ω -1 Oxidation

22. 7.Oxidation of Alicyclic Carbon Atoms OH Minoxidil 4’-Hydroxy minoxidil

32. 9.Oxidation of Alcohol,Carbonyl and Carboxylic Acid. Alcohol Dehydrogenase Aldehyde Dehydrogenase

33. Reductive Reactions 1. Reduction of Carbonyls (Aldehyde and Ketones) H 2 O Aldehyde

34. Ketones Methadone Methadol

35. 2.Reduction of Nitro Compounds

36. 3.Reduction of Azo Compounds

37. Hydrolytic Reactions 1.Ester Hydrolysis Enalaprit

38. 2.Amide Hydrolysis + NH 2 CH 2 CH 2 N(C 2 H 5 ) 2 Procainamide

39. Carbamazepine Iminostilbine H

40. 3.EPOXIDE HYDROLASE

41. PHASE II METABOLIC PATHWAYS

42. D+ ENDO X D X + ENDO PHASE 2 METABOLISM A molecule endogenous to the body donates a portion of itself to the foreign molecule

43. PHASE II REACTIONS Glucuronidation Sulfate Conjugation Acetylation Glycine Conjugation Methylation Transulfuration Glutathione Conjugation Mercapturic Acid Synthesis

44. GLUCURONIDATION Uridine-5’diphospho-  -D-glucuronic Acid The microsomal enzyme glucuronyl transferase conducts the donation of glucuronic acid from the endogenously synthesized UDPGA to various substrates to form glucuronide conjugates. Examples of such substrates are morphine and acetaminophen.

45. SYNTHESIS OF UDPGA

46. Glucuronidation of Benzoic Acid UGT= UDP-  -D-Glucuronsyltransferase

47. Glucuronidation of Aniline

48. Glucuronidation of p -Hydroxyacetanilid

50. 3’-Phosphoadenosine-5’-phosphosulfate (PAPS) The cytosolic enzyme sulfotransferase conducts the donation of sulfate from the endogenously synthesized PAPS to various substrates to form sulfate conjugates. An example of such substrate is acetaminophen.

51. SYNTHESIS OF PAPS

52. Sulfate Conjugation of p -Hydroxyacetanilid PAP: 3’-phosphoadenosine- 5’-phosphate

53. AMINO ACID CONJUGATION RCOOH + CoA-SH Acid:CoA ligase RCO -S-CoA RCO -S-CoA + NH 2 CH 2 COOH RCO NHCH 2 COOH N-acyl transferase ATP Glycine Glycine conjugate (mitochondria) Acyl CoA

54. Salicycluric Acid is the Glycine Conjugate of Aspirin Salicyluric acid, the glycine conjugate of salicyclic acid, is the main metabolite of aspirin. Approximately 76% of aspirin is metabolized through amino acid conjugation.

56. Acetyl CoA Various acetylases, for examples, choline acetylase and N-acetyl transferase, all soluble enzymes, conduct the transfer of the acetyl group of acetyl CoA to various substrates. For example, N-acetylation of isoniazid. Genetic polyporphism occurs with N-acetyltransferase.

57. N-Acetyltransferase

58. METHYLATION S-Adenosylmethionine Cytosolic enzymes such as catechol-O-methyl transferase (COMT) and phenylethanolamine-N-methyl transferase (PNMT) conducts the donation of the methyl group from the endogenously synthesized SAM to various substrates to form methylated conjugates. Norepinephrine is N-methylated by PNMT to form epinephrine. Norepinephrine, epinephrine, dopamine, and L-DOPA are O-methylated by COMT.

60. N-Methyltransferases PNMT- Phenylethanolamine-N-methyltransferase Norepinephrine Epinephrine PNMT SAM

61. O-Methylation Of Catecholamines COMT- catechol-O-methyltransferase

62. O-Methylation of Norepinephrine COMT- catechol-O-methyltransferase

63. S-Methylation of 6-Mercaptopurine TPMT - thiopurinemethyltransferase; some individuals are deficient in this enzyme that is critically important for the metabolism of this agent

64. GLUTATHIONE CONJUGATION Glutathione  -glutamyl-cysteinyl-glycine Active site of a GST: Nucleophile

65. DRUG INTERACTION WITH GLUTATHIONE mercapturate metabolite of drug (S-substituted glutathione conjugate) Glutathione-S-transferase ץ -glutamyl transpeptidase Cysteine-glycine conjugate Cysteinyl glycinase Cysteine conjugate N-acetylase

67. METABOLISM OF NAPHTHALENE BY GLUTATHIONE CONJUGATION

69. TRANSULFURATION Inactive Mediated by  mercaptopyruvate sulfurtransferase

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