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Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
Metabolism final
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Metabolism final

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  • 1. DRUG METABOLISM
  • 2. Definition of Metabolism
    • Metabolism is defined as the sum total of all chemical reactions that occur in the body.
    • In Other Words
    • Metabolism of drugs is defined as the conversion from one chemical form to another.
  • 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
  • 5. Organ Sites of Drug Metabolism
    • Liver
    • Small intestine
    • Kidney
    • Skin
    • Lungs
    • Plasma
    • All organs of the body
  • 6. CELLULAR SITES OF DRUG METABOLISM
  • 7. Cellular Sites Of Drug Metabolism
    • Cytosol
    • Mitochondria
    • Lysosomes
    • Smooth endoplasmic reticulum (microsomes)
  • 8. Drug metabolising enzymes
  • 9.
    • The enzymes are broadly divided into two
    • categories
    • Microsomal
    • Non Microsomal
  • 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
  • 11.  
  • 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
  • 15. Oxidative Reactions
    • Oxidation Of Aromatic Carbon Atoms
    acetanilide p -hydroxyacetanilide
  • 16.  
  • 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
  • 23. 8.Oxidation of carbon-heteroatom systems A.Carbon-Nitrogen systems
    • N-Dealkylation
    • Oxidative Deamination
    • N-Oxide Formation
    • N-Hydroxylation
    B.Carbon-Sulfur Systems
    • S-Dealkylation
    • Desulfuration
    • S-Oxidation
    C.Carbon-Oxygen Systems
    • O-Dealkylation
  • 24. A.Carbon-Nitrogen systems
    • N-Dealkylation
  • 25.
    • Oxidative Deamination
  • 26.
    • N-Oxide Formation
  • 27.
    • N-Hydroxylation
  • 28. B.Carbon-Sulfur Systems
    • S-Dealkylation
  • 29.
    • Desulfuration
  • 30.
    • S-Oxidation
  • 31. C.Carbon-Oxygen Systems
    • O-Dealkylation
  • 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
  • 49. SULFATE CONJUGATION
    • Conducted by the soluble enzyme sulfotransferase
    • Endogenous donor molecule to conjugation is 3’-phosphoadenosine-5’-phosphosulfate (PAPS)
    • Conjugates are ethereal in character
    • Noninducible
  • 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.
  • 55. N-ACETYLATION
    • A soluble enzyme
    • Isoniazid is a substrate
    • Genetic variation occurs
      • Some individuals are fast acetylators
      • Some individuals are slow acetylators
    • Acetyl coenzyme A is the endogenous donor molecule
  • 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.
  • 59. Methyltransferases
    • A family of soluble enzymes that conducts
      • N-methylation; N-CH 3
      • O-methylation; O-CH 3
      • S-methylation; S-CH 3
    • S-adenosylmethionine (SAM)is the endogenous donor molecule. It is demethylated to S-adenosylhomocysteine
  • 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
  • 66. MERCAPTURIC ACID FORMATION
    • Conjugation of substrate to glutathione by the enzyme glutathione transferase
    • Hydrolytic removal of glutamic acid by glutamyl transpeptidase
    • Hydrolytic removal of glycine by cysteinyl glycinase
    • Acetylation of the cysteinyl substrate by N-acetyltransferase to form the N-acetylated cysteinyl conjugate of substrate; substrate referred to as a “mercapturate”
  • 67. METABOLISM OF NAPHTHALENE BY GLUTATHIONE CONJUGATION
  • 68.  
  • 69. TRANSULFURATION Inactive Mediated by  mercaptopyruvate sulfurtransferase
  • 70. Q & A
    • Those are my thoughts.
      • What are yours?
  • 71. THANK YOU

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