Metabolism final

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Metabolism final

  1. 1. DRUG METABOLISM
  2. 2. Definition of Metabolism <ul><li>Metabolism is defined as the sum total of all chemical reactions that occur in the body. </li></ul><ul><li>In Other Words </li></ul><ul><li>Metabolism of drugs is defined as the conversion from one chemical form to another. </li></ul>
  3. 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. 4. ORGAN SITES OF DRUG METABOLISM
  5. 5. Organ Sites of Drug Metabolism <ul><li>Liver </li></ul><ul><li>Small intestine </li></ul><ul><li>Kidney </li></ul><ul><li>Skin </li></ul><ul><li>Lungs </li></ul><ul><li>Plasma </li></ul><ul><li>All organs of the body </li></ul>
  6. 6. CELLULAR SITES OF DRUG METABOLISM
  7. 7. Cellular Sites Of Drug Metabolism <ul><li>Cytosol </li></ul><ul><li>Mitochondria </li></ul><ul><li>Lysosomes </li></ul><ul><li>Smooth endoplasmic reticulum (microsomes) </li></ul>
  8. 8. Drug metabolising enzymes
  9. 9. <ul><li>The enzymes are broadly divided into two </li></ul><ul><li>categories </li></ul><ul><li>Microsomal </li></ul><ul><li>Non Microsomal </li></ul>
  10. 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
  12. 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
  13. 14. Phase I Reactions OXIDATION REDUCTION HYDROLYSIS
  14. 15. Oxidative Reactions <ul><li>Oxidation Of Aromatic Carbon Atoms </li></ul>acetanilide p -hydroxyacetanilide
  15. 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
  16. 18. 3.Oxidation of Benzylic Carbon Atom Tolbutamide Primary Carbinol Corresponding aldehyde Corresponding Carboxylic acid 2 OH
  17. 19. 4.Oxidation of Allylic Carbon Atoms Hexobarbital 3-hydroxy Hexobarbital Allylic Carbon Atom
  18. 20. 5.Oxidation of Carbon Atoms Alpha to Carbonyls and imines OH Diazepam 3-Hydroxy diazepam
  19. 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
  20. 22. 7.Oxidation of Alicyclic Carbon Atoms OH Minoxidil 4’-Hydroxy minoxidil
  21. 23. 8.Oxidation of carbon-heteroatom systems A.Carbon-Nitrogen systems <ul><li>N-Dealkylation </li></ul><ul><li>Oxidative Deamination </li></ul><ul><li>N-Oxide Formation </li></ul><ul><li>N-Hydroxylation </li></ul>B.Carbon-Sulfur Systems <ul><li>S-Dealkylation </li></ul><ul><li>Desulfuration </li></ul><ul><li>S-Oxidation </li></ul>C.Carbon-Oxygen Systems <ul><li>O-Dealkylation </li></ul>
  22. 24. A.Carbon-Nitrogen systems <ul><li>N-Dealkylation </li></ul>
  23. 25. <ul><li>Oxidative Deamination </li></ul>
  24. 26. <ul><li>N-Oxide Formation </li></ul>
  25. 27. <ul><li>N-Hydroxylation </li></ul>
  26. 28. B.Carbon-Sulfur Systems <ul><li>S-Dealkylation </li></ul>
  27. 29. <ul><li>Desulfuration </li></ul>
  28. 30. <ul><li>S-Oxidation </li></ul>
  29. 31. C.Carbon-Oxygen Systems <ul><li>O-Dealkylation </li></ul>
  30. 32. 9.Oxidation of Alcohol,Carbonyl and Carboxylic Acid. Alcohol Dehydrogenase Aldehyde Dehydrogenase
  31. 33. Reductive Reactions 1. Reduction of Carbonyls (Aldehyde and Ketones) H 2 O Aldehyde
  32. 34. Ketones Methadone Methadol
  33. 35. 2.Reduction of Nitro Compounds
  34. 36. 3.Reduction of Azo Compounds
  35. 37. Hydrolytic Reactions 1.Ester Hydrolysis Enalaprit
  36. 38. 2.Amide Hydrolysis + NH 2 CH 2 CH 2 N(C 2 H 5 ) 2 Procainamide
  37. 39. Carbamazepine Iminostilbine H
  38. 40. 3.EPOXIDE HYDROLASE
  39. 41. PHASE II METABOLIC PATHWAYS
  40. 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
  41. 43. PHASE II REACTIONS Glucuronidation Sulfate Conjugation Acetylation Glycine Conjugation Methylation Transulfuration Glutathione Conjugation Mercapturic Acid Synthesis
  42. 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.
  43. 45. SYNTHESIS OF UDPGA
  44. 46. Glucuronidation of Benzoic Acid UGT= UDP-  -D-Glucuronsyltransferase
  45. 47. Glucuronidation of Aniline
  46. 48. Glucuronidation of p -Hydroxyacetanilid
  47. 49. SULFATE CONJUGATION <ul><li>Conducted by the soluble enzyme sulfotransferase </li></ul><ul><li>Endogenous donor molecule to conjugation is 3’-phosphoadenosine-5’-phosphosulfate (PAPS) </li></ul><ul><li>Conjugates are ethereal in character </li></ul><ul><li>Noninducible </li></ul>
  48. 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.
  49. 51. SYNTHESIS OF PAPS
  50. 52. Sulfate Conjugation of p -Hydroxyacetanilid PAP: 3’-phosphoadenosine- 5’-phosphate
  51. 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
  52. 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.
  53. 55. N-ACETYLATION <ul><li>A soluble enzyme </li></ul><ul><li>Isoniazid is a substrate </li></ul><ul><li>Genetic variation occurs </li></ul><ul><ul><li>Some individuals are fast acetylators </li></ul></ul><ul><ul><li>Some individuals are slow acetylators </li></ul></ul><ul><li>Acetyl coenzyme A is the endogenous donor molecule </li></ul>
  54. 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.
  55. 57. N-Acetyltransferase
  56. 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.
  57. 59. Methyltransferases <ul><li>A family of soluble enzymes that conducts </li></ul><ul><ul><li>N-methylation; N-CH 3 </li></ul></ul><ul><ul><li>O-methylation; O-CH 3 </li></ul></ul><ul><ul><li>S-methylation; S-CH 3 </li></ul></ul><ul><li>S-adenosylmethionine (SAM)is the endogenous donor molecule. It is demethylated to S-adenosylhomocysteine </li></ul>
  58. 60. N-Methyltransferases PNMT- Phenylethanolamine-N-methyltransferase Norepinephrine Epinephrine PNMT SAM
  59. 61. O-Methylation Of Catecholamines COMT- catechol-O-methyltransferase
  60. 62. O-Methylation of Norepinephrine COMT- catechol-O-methyltransferase
  61. 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
  62. 64. GLUTATHIONE CONJUGATION Glutathione  -glutamyl-cysteinyl-glycine Active site of a GST: Nucleophile
  63. 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
  64. 66. MERCAPTURIC ACID FORMATION <ul><li>Conjugation of substrate to glutathione by the enzyme glutathione transferase </li></ul><ul><li>Hydrolytic removal of glutamic acid by glutamyl transpeptidase </li></ul><ul><li>Hydrolytic removal of glycine by cysteinyl glycinase </li></ul><ul><li>Acetylation of the cysteinyl substrate by N-acetyltransferase to form the N-acetylated cysteinyl conjugate of substrate; substrate referred to as a “mercapturate” </li></ul>
  65. 67. METABOLISM OF NAPHTHALENE BY GLUTATHIONE CONJUGATION
  66. 69. TRANSULFURATION Inactive Mediated by  mercaptopyruvate sulfurtransferase
  67. 70. Q & A <ul><li>Those are my thoughts. </li></ul><ul><ul><li>What are yours? </li></ul></ul>
  68. 71. THANK YOU

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