Drug metabolism


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Drug metabolism

  1. 1. DRUG METABOLISM www.freelivedoctor.com
  2. 2. Transformation of Xenobiotics by Biological Systems www.freelivedoctor.com
  3. 3. IMPLICATIONS FOR DRUG METABOLISM www.freelivedoctor.com
  4. 4. IMPLICATIONS FOR DRUG METABOLISM 1. Termination of drug action 2. Activation of prodrug 3. Bioactivation and toxication 4. Carcinogenesis 5. Tetratogenesis www.freelivedoctor.com
  5. 5. Termination of Drug Action www.freelivedoctor.com tropic acid and tropine atropine propranolol  hydroxypropranolol (active) (active)
  6. 6. Termination of Drug Action Conversion of drug to active metabolite to active metabolite to inactive metabolite www.freelivedoctor.com
  7. 7. Activation of Prodrug www.freelivedoctor.com Dopamine L-dopa
  8. 8. Inactive Terfenadine is Converted to its Active Metabolite Fexofenadine terfenadine fexofenadine activation of prodrug www.freelivedoctor.com
  9. 9. Some Xenobiotics Are Metabolized to Carcinogenic Agents <ul><li>3,4 Benzopyrene </li></ul><ul><li>Aflatoxin </li></ul><ul><li>N-Acetylaminoflluorene </li></ul>Metabolites of these agents interact with DNA carcinogenesis www.freelivedoctor.com
  10. 10. Small Amounts of Acetaminophen is Converted to the Reactive Metabolite N-Acetylbenzoquinoneimine Bioactivation of acetaminophen; under certain conditions, the electrophile N-acetylbenzoquinoneimine reacts with tissue macromolecules, causing liver necrosis. bioactivation www.freelivedoctor.com
  11. 11. Thalidomide is a Teratogen <ul><ul><li>THALIDOMIDE: Fetal malformations in humans, monkeys, and rats occur due to metabolism of the parent compound to a teratogen. This occurs very early in gestation. </li></ul></ul>teratogensis www.freelivedoctor.com
  12. 12. FACTORS AFFECTING DRUG METABOLISM www.freelivedoctor.com
  13. 13. Factors Affecting Drug Metabolism <ul><li>Age </li></ul><ul><li>Diet </li></ul><ul><li>Genetic Variation </li></ul><ul><li>State of Health </li></ul><ul><li>Gender </li></ul><ul><li>Degree of Protein Binding </li></ul><ul><li>Species Variation </li></ul><ul><li>Substrate Competition </li></ul><ul><li>Enzyme Induction </li></ul><ul><li>Route of Drug Administration </li></ul>www.freelivedoctor.com
  14. 14. Factors Affecting Drug Metabolism <ul><li>Route of drug administration </li></ul><ul><ul><li>Oral versus systemic administration </li></ul></ul>www.freelivedoctor.com
  15. 15. Many Drugs Undergo First Pass Metabolism Upon Oral Administration <ul><li>Oral administration </li></ul><ul><li>Drug travels from gut to portal vein to liver </li></ul><ul><li>Vigorous metabolism occurs in the liver. Little drug gets to the systemic circulation </li></ul><ul><li>The wall of the small intestine also contributes to first pass metabolism </li></ul>www.freelivedoctor.com
  16. 16. ORGAN SITES OF DRUG METABOLISM www.freelivedoctor.com
  17. 17. 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>www.freelivedoctor.com
  18. 18. CELLULAR SITES OF DRUG METABOLISM www.freelivedoctor.com
  19. 19. 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>www.freelivedoctor.com
  20. 20. KINETICS OF DRUG METABOLISM www.freelivedoctor.com
  21. 21. Velocity Of Metabolism Of A Drug D:summer1Kmx1.pzm www.freelivedoctor.com
  22. 22. Velocity Of Metabolism Of A Drug Kmx2.pzm www.freelivedoctor.com
  23. 23. First Order Metabolism v = Vmax [C] Km + [C] When Km >>> [C], then v = Vmax [C] , Km and v  [C] Metabolism of the drug is a first order process. A constant fraction of the remaining drug is metabolized per unit time. Most drugs are given at concentrations smaller than the Km of the enzymes of their metabolism. A drug may be given in doses that produce blood concentrations less than the Km of the enyzme for the drug. www.freelivedoctor.com
  24. 24. Velocity Of Metabolism Of A Drug Kmx2.pzm www.freelivedoctor.com
  25. 25. Zero Order Metabolism v = Vmax [C] K m + [C] When [C] >>> Km, then v = Vmax [C] , [C] and v = Vmax Metabolism of the drug is a zero order process. A constant amount of the remaining drug is metabolized per unit time. Phenytoin undergoes zero order metabolism at the doses given. A drug may be given in doses that produce blood concentrations greater than the Km of the enyzme for the drug. www.freelivedoctor.com
  26. 26. Velocity Of Metabolism Of A Drug Kmx2.pzm www.freelivedoctor.com
  27. 27. Velocity Of Metabolism Of Three Drugs By The Same Enzyme www.freelivedoctor.com
  28. 28. PHASES OF DRUG METABOLISM www.freelivedoctor.com
  29. 29. 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 www.freelivedoctor.com
  30. 30. Phase I Reactions OXIDATION REDUCTION HYDROLYSIS www.freelivedoctor.com
  31. 31. Phase II Metabolism A molecule endogenous to the body donates a portion of itself to the foreign molecule www.freelivedoctor.com D+ ENDO X D X + ENDO
  32. 32. Patterns of Drug Metabolism <ul><li>Parent molecule  Phase 1 metabolism </li></ul><ul><li>Phase 1 metabolite  Phase 2 metabolism </li></ul><ul><li>Parent molecule  Phase 2 metabolism </li></ul><ul><li>Phase 2 metabolite  Phase 1 metabolism </li></ul>Some drugs are not metabolized, for example, gallamine and decamethonium. Atracurium undergoes spontaneous hydrolysis. www.freelivedoctor.com
  33. 33. PHASE I METABOLIC PATHWAYS www.freelivedoctor.com
  34. 34. Microsomal Oxidation www.freelivedoctor.com
  35. 35. Preparation Of Microsomes www.freelivedoctor.com
  36. 36. Cytochrome P450 fp = NADPH cytochrome P450 reductase, or NADH cytochrome b5 reductase www.freelivedoctor.com
  37. 37. Oxidation Of Drugs By Cytochrome P450 www.freelivedoctor.com
  38. 38. Oxidation Of Drugs By Cytochrome P450 www.freelivedoctor.com
  39. 39. Aliphatic Oxidation www.freelivedoctor.com
  40. 40. Aromatic Hydroxylation (1) acetanilid p -hydroxyacetanilid www.freelivedoctor.com
  41. 41. Aromatic Hydroxylation (2) www.freelivedoctor.com
  42. 42. N-Dealkylation www.freelivedoctor.com
  43. 43. O-Dealkylation www.freelivedoctor.com
  44. 44. S-Demethylation www.freelivedoctor.com
  45. 45. Oxidative Deamination www.freelivedoctor.com
  46. 46. S-Oxidation www.freelivedoctor.com
  47. 47. N-Oxidation www.freelivedoctor.com
  48. 48. N-Hydroxylation www.freelivedoctor.com
  49. 49. N-Hydroxylation of AAF N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent www.freelivedoctor.com
  50. 50. Oxidative Dehalogenation www.freelivedoctor.com
  51. 51. Desulfuration www.freelivedoctor.com
  52. 52. Desulfuration www.freelivedoctor.com
  53. 53. ISOENZMYES OF CYTOCHROME P450 CYP1A1 CYP1A2 CYP2A6 CYP2B_ CYP2C9 CYP2C19 CYP2D6 CYP2AE1 CYP3A4 CYP3A5 CYP3A7 CYP4A_ www.freelivedoctor.com
  54. 54. Cytochrome P450 3A4 (CYP3A4) www.freelivedoctor.com
  55. 55. CYP3A4 <ul><li>CYP3A4 is responsible for metabolism of 60% of all drugs </li></ul><ul><li>It comprises approximately 28% of hepatic cytochrome P450 </li></ul><ul><li>Metabolizes terfenadine </li></ul><ul><li>Ingestion of grapefruit juice reduces expression of this enzyme </li></ul><ul><li>Inhibited by some regularly used drugs </li></ul>www.freelivedoctor.com
  56. 56. Some Drugs That Inhibit CYP3A4 <ul><li>Macrolide antibiotics </li></ul><ul><ul><li>Erythromycin </li></ul></ul><ul><ul><li>Clarithromycin </li></ul></ul><ul><ul><li>Other such agents </li></ul></ul><ul><li>Antifungal agents </li></ul><ul><ul><li>Ketoconazole </li></ul></ul><ul><ul><li>Itraconazole </li></ul></ul><ul><ul><li>Other such agents </li></ul></ul><ul><li>HIV protease inhibitors </li></ul>www.freelivedoctor.com
  57. 57. CYP3A4 <ul><li>Ketoconazole and terfenadine can produce a drug interaction with fatal consequences. </li></ul>www.freelivedoctor.com
  59. 59. AN INGREDIENT IN GRAPEFRUIT JUICE INHIBITS CYP3A4 www.freelivedoctor.com
  60. 60. Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression J.Clin. Invest. 99:10, p.2545-53, 1997 Hours www.freelivedoctor.com
  61. 61. 6',7', - Dihydroxybergamottin www.freelivedoctor.com
  62. 62. Grapefruit Juice Consumption Blocks Terfenadine Metabolism to Fexofenadine www.freelivedoctor.com X
  63. 63. CYP3A4 And P-Glycoprotein <ul><li>P-Glycoprotein and CYP3A4 control oral bioavailability of many drugs </li></ul><ul><li>P-Glycoprotein and CYP3A4 share many substrates and inhibitors </li></ul>www.freelivedoctor.com
  64. 64. CYP2D6 is an Enzyme with Polymorphisms <ul><li>Approximately 70 nucleotide polymorphisms are known </li></ul><ul><li>Four phenotype subpopulations of metabolizers * </li></ul><ul><ul><li>Poor metabolizers (PM) </li></ul></ul><ul><ul><li>Intermediate metabolizers (IM) </li></ul></ul><ul><ul><li>Extensive metabolizers (EM) </li></ul></ul><ul><ul><li>Ultrarapid metabolizers (UM) </li></ul></ul><ul><li>Variations according to racial background </li></ul><ul><li>More than 65 commonly used drugs are substrates </li></ul><ul><li>Codeine is a well known substrate </li></ul>* The Pharmacological Basis of Therapeutics www.freelivedoctor.com
  65. 65. Codeine is a Substrate of CYP2D6 Consider the variation in codeine’s metabolism among PM, IM, EM, UM individuals -CH 3 (methyl morphine) www.freelivedoctor.com
  66. 66. CYP2C9 <ul><li>Metabolizes some 16 commonly used drugs </li></ul><ul><li>Warfarin and phenytoin are among the substrates </li></ul><ul><li>Two allelic variants are known: metabolizes substrates 5% to 12% of the wild type enzyme </li></ul><ul><ul><li>Warfarin clearance is greatly reduced in individuals possessing the allelic variants </li></ul></ul><ul><li>Dose adjustments are required for drugs in individuals who have the mutant enzymes </li></ul>www.freelivedoctor.com
  67. 67. CYP2C 19 <ul><li>S-mephenytoin is a substrate </li></ul><ul><ul><li>(4-hydroxylation at the phenyl ring ) </li></ul></ul><ul><li>As much as eight allelic variants identified </li></ul><ul><ul><li>All are nonfunctional proteins </li></ul></ul><ul><li>Poor metabolizers of S-mephenytoin lack 4-hydroxylase activity, but N-demethylation to nirvanol is an alternative but slow metabolic pathway </li></ul><ul><ul><li>Dose adjustments must be made for poor metabolizers of S-mephenytoin and for other drugs that are substrates for this enzyme </li></ul></ul>www.freelivedoctor.com
  68. 68. CYP1A1 <ul><li>Polycyclic hydrocarbons are among its substrates </li></ul><ul><li>Inducers include </li></ul><ul><ul><li>Polycyclic hydrocarbons such as 3,4,-benzopyrene, 3-methylcholanthrene, etc. </li></ul></ul><ul><ul><li>Charcoal broiled foods (polycyclic hydrocarbons) </li></ul></ul>www.freelivedoctor.com
  69. 69. CIMETIDINE Inhibits CYP450 Metabolism Of Many Drugs Warfarin Phenytoin Metoprolol Labetalol Quinidine Caffeine Lidocaine Theophylline Alprazolam Diazepam Flurazepam Triazolam Chlordiazepoxide Carbamazepine Quinidine Ethanol Tricyclic antidepressants Metronidazole Calcium channel blockers Diazepam Sulfonylureas www.freelivedoctor.com
  71. 71. Nonmicrosomal Oxidations Alcohol dehydrogenation is conducted by the enzyme alcohol dehydrogenase (cytosolic) Aldehyde dehydrogenation is conducted by the enzyme aldehyde dehydrogenase (cytosol and mitochondria) Xanthine oxidation is conducted by the cytosolic enzyme xanthine oxidase. Diamine oxidase (cytosolic) oxidizes histamine and diamines such as cadaverine and putrescine. Monoamine oxidation is conducted by mitochondrial monoamine oxidase (norepinephrine, epinephrine, dopamine and serotonin are endogenous substrates. www.freelivedoctor.com
  72. 72. Monoamine Oxidase Metabolism of Serotonin www.freelivedoctor.com
  73. 73. Some Popular Substrates of Monoamine Oxidase <ul><li>Serotonin </li></ul><ul><li>Epinephrine </li></ul><ul><li>Norepinephrine </li></ul><ul><li>Dopamine </li></ul><ul><li>Tyramine (found in certain foods) </li></ul>www.freelivedoctor.com
  74. 74. Diamine Oxidase cadaverine www.freelivedoctor.com
  75. 75. Alcohol Dehydrogenase <ul><li>A soluble enzyme, found almost exclusively in the parenchymal cells of the liver </li></ul><ul><li>Converts ethanol to acetaldehyde </li></ul><ul><li>Converts methanol to formaldehyde </li></ul><ul><li>Converts ethylene glycol to its respective aldehyde metabolites </li></ul><ul><li>Is inhibited by pyrazole </li></ul>www.freelivedoctor.com
  76. 76. Alcohol Dehydrogenase CH 3 CH 2 OH + NAD +  CH 3 CHO + NADH + H + ethanol acetaldehyde www.freelivedoctor.com
  77. 77. Aldehyde Dehydrogenase CH 3 CHO + NAD +  CH 3 COOH + NADH + H + acetaldehyde acetate www.freelivedoctor.com
  78. 78. XANTHINE OXIDASE www.freelivedoctor.com
  79. 79. Xanthine Oxidase www.freelivedoctor.com
  80. 80. REDUCTION www.freelivedoctor.com
  81. 81. Nitro Reduction Microsomes and cytosol www.freelivedoctor.com
  82. 82. Nitro Reduction www.freelivedoctor.com
  83. 83. Azo Reduction Microsomes and cytosol www.freelivedoctor.com
  84. 84. Azo Reduction Microsomes and cytosol www.freelivedoctor.com
  85. 85. Alcohol Dehydrogenation Cytosol www.freelivedoctor.com
  86. 86. DIHYDROPYRIMIDINE DEHYDROGENASE <ul><li>DPYD </li></ul><ul><ul><li>Inactivates 5-fluorouracil by ring reduction </li></ul></ul><ul><ul><li>Inherited deficiency of this enzyme leads to 5-fluorouracil toxicity </li></ul></ul><ul><ul><li>Enzyme deficiency can be detected by enzymatic or molecular assays using white blood cells </li></ul></ul>5-fluorouracil www.freelivedoctor.com 5-Fluorouracil 5-Fluoro-5,6-dihydrouracil DPYD
  87. 87. HYDROLYSIS www.freelivedoctor.com
  88. 88. Amide Hydrolysis Microsomes and cytosol www.freelivedoctor.com
  89. 89. Ester Hydrolysis Microsomes and cytosol www.freelivedoctor.com
  90. 90. Ester Hydrolysis Microsomes and cytosol Enalaprit www.freelivedoctor.com
  91. 91. EPOXIDE HYDROLASE www.freelivedoctor.com
  92. 92. Epoxide Hydrolase <ul><li>A microsomal enzyme </li></ul>www.freelivedoctor.com
  93. 93. Epoxide Hydrolase www.freelivedoctor.com
  94. 94. www.freelivedoctor.com
  95. 95. PHASE II METABOLIC PATHWAYS www.freelivedoctor.com
  96. 96. D+ ENDO X D X + ENDO PHASE 2 METABOLISM A molecule endogenous to the body donates a portion of itself to the foreign molecule www.freelivedoctor.com
  97. 97. PHASE II REACTIONS Glucuronidation Sulfate Conjugation Acetylation Glycine Conjugation Methylation Transulfuration Glutathione Conjugation Mercapturic Acid Synthesis www.freelivedoctor.com
  98. 98. GLUCURONIDATION www.freelivedoctor.com
  99. 99. Uridine-5’-  -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. www.freelivedoctor.com
  100. 100. UDP-  -D-Glucuronsyltransferase <ul><li>Is also called glucuronyl transferase </li></ul><ul><li>A microsomal enzyme </li></ul><ul><li>Substrates are called aglycones </li></ul><ul><li>Conducts phase 2 metabolic reactions </li></ul><ul><li>Products are called glucuronides </li></ul><ul><li>Glucuronides formed </li></ul><ul><ul><li>RN- G ; RO- G ; RCOO- G ; RS- G ; RC- G </li></ul></ul><ul><li>Bilirubin is an endogenous substrate </li></ul><ul><li>Induced by phenobarbital </li></ul>www.freelivedoctor.com
  101. 101. Glucuronidation of Benzoic Acid UGT= UDP-  -D-Glucuronsyltransferase www.freelivedoctor.com
  102. 102. Glucuronidation of Aniline www.freelivedoctor.com
  103. 103. Glucuronidation of p -Hydroxyacetanilid www.freelivedoctor.com
  104. 104. Morphine Metabolism A small amount of morphine undergoes N-demethylation Morphine  Morphine -6-glucuronide (active metabolite) Morphine  Morphine -3-glucuronide (inactive metabolite) www.freelivedoctor.com
  105. 105. Morphine Metabolism Morphine -3-glucuronide is the major metabolite www.freelivedoctor.com
  106. 106. Induction Of UDP-  -D-Glucuronyl Transferase <ul><li>Induced by phenobarbital </li></ul><ul><li>Induced by 3-methylcholanthrene </li></ul>www.freelivedoctor.com
  107. 107. Glucuronidation in the Cat <ul><li>The cat can glucuronidate bilirubin but cannot glucuronidate phenolic compounds such as phenol and napthol </li></ul>www.freelivedoctor.com
  108. 108. SULFATE CONJUGATION www.freelivedoctor.com
  109. 109. 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>www.freelivedoctor.com
  110. 110. 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. www.freelivedoctor.com
  111. 111. Sulfate Conjugation of p -Hydroxyacetanilid PAP: 3’-phosphoadenosine- 5’-phosphate www.freelivedoctor.com
  112. 112. MINOXIDIL METABOLISM MINOXIDIL N-O-GLUCURONIDE (inactive metabolite) www.freelivedoctor.com MINOXIDIL (inactive) MINOXIDIL N-O-SULFATE (active metabolite)
  113. 113. Species Differences in Sulfate Conjugation <ul><li>Some species are deficient in the sulfate conjugation pathway </li></ul><ul><ul><li>Pig </li></ul></ul><ul><ul><li>Opposum </li></ul></ul>www.freelivedoctor.com
  114. 114. N-ACETYLATION www.freelivedoctor.com
  115. 115. N-Acetyltransferase <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>www.freelivedoctor.com
  116. 116. 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. www.freelivedoctor.com
  117. 117. N-Acetyltransferase www.freelivedoctor.com
  118. 118. N-Acetyltransferase <ul><li>The dog cannot acetylate aromatic amino compounds because it lacks the appropriate isoenzyme of NAT </li></ul>www.freelivedoctor.com
  119. 119. SUGAR CONJUGATION www.freelivedoctor.com
  120. 120. Conversion of 6-Mercaptopurine to a Nucleotide www.freelivedoctor.com
  121. 121. METHYLATION www.freelivedoctor.com
  122. 122. 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. www.freelivedoctor.com
  123. 123. 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>www.freelivedoctor.com
  124. 124. N-Methyltransferases PNMT- Phenylethanolamine-N-methyltransferase www.freelivedoctor.com Norepinephrine Epinephrine PNMT SAM
  125. 125. O-Methylation Of Catecholamines COMT- catechol-O-methyltransferase www.freelivedoctor.com
  126. 126. O-Methylation of Norepinephrine COMT- catechol-O-methyltransferase www.freelivedoctor.com
  127. 127. S-Methylation of 6-Mercaptopurine TPMT - thiopurinemethyltransferase; some individuals are deficient in this enzyme that is critically important for the metabolism of this agent www.freelivedoctor.com
  128. 128. METABOLISM OF MERCAPTOPURINE (1) <ul><li>TMPT -Thiomethylpurinetransferase </li></ul><ul><ul><li>Conducts S-methylation of the substrate </li></ul></ul><ul><ul><li>Found in RBC’s </li></ul></ul><ul><ul><li>Isoforms exist </li></ul></ul><ul><ul><ul><li>active enzyme </li></ul></ul></ul><ul><ul><ul><li>inactive enzyme </li></ul></ul></ul>www.freelivedoctor.com 6-Mercaptopurine 6-Methylmercaptopurine TMPT
  129. 129. AMINO ACID CONJUGATION www.freelivedoctor.com
  130. 130. AMINO ACID CONJUGATION (mitochondria) www.freelivedoctor.com
  131. 131. Multiple Metabolic Pathways Exist for Aspirin’s Metabolism Hydolysis of aspirin produces salicyclic acid, as seen in the next slide www.freelivedoctor.com
  132. 132. Salicyluric 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. www.freelivedoctor.com
  133. 133. Acetyl Salicylic Acid (Aspirin) Metabolism <ul><li>Salicylic acid the hydrolytic product of acetyl salicylic acid. Salicylic acid is further metabolized </li></ul><ul><li>Salicyl uric acid is the glycine conjugate and the main metabolite of aspirin. About 75% of aspirin is metabolized by this pathway </li></ul><ul><li>Other metabolites of aspirin </li></ul><ul><ul><li>the acyl glucuronide conjugate of salicylic acid (salicylic acid glucuronide) </li></ul></ul><ul><ul><li>the phenol glucuronide conjugate of salicylic acid (salicyl phenol glucuronide) </li></ul></ul><ul><ul><li>the ring hydroxylated product of salicylic acid (gentisic acid) </li></ul></ul><ul><ul><li>the ring hydroxylated product of the glycine conjugate (gentisuric acid </li></ul></ul>www.freelivedoctor.com
  134. 134. TRANSULFURATION www.freelivedoctor.com
  135. 135. TRANSULFURATION www.freelivedoctor.com
  136. 136. GLUTATHIONE CONJUGATION www.freelivedoctor.com
  137. 137. DRUG INTERACTION WITH GLUTATHIONE mercapturate metabolite of drug www.freelivedoctor.com
  138. 138. 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>www.freelivedoctor.com
  139. 139. ACETAMINOPHEN METABOLISM www.freelivedoctor.com
  140. 140. Bioactivation of Acetaminophen www.freelivedoctor.com
  141. 141. ACETAMINOPHEN AND ITS PHASE II METABOLITES The sulfate and glucuronide conjugates of acetaminophen are the major metabolites. High doses of acetaminophen can exhaust the metabolic pathways that produce these conjugates, allowing more of the parent drug to undergo the phase I metabolic pathway which is involved in bioactivation and toxication. www.freelivedoctor.com
  142. 142. ACETAMINOPHEN AND ITS PHASE I METABOLITES www.freelivedoctor.com
  143. 143. ACETAMINOPHEN AND ITS PHASE I METABOLITES- pt2 The minor metabolite (4% of acetaminophen), N-hydroxyacetaminophen , is always produced by microsomal cytochrome P450. It rearranges to the electrophile N-acetylbenzoquinoneimine, which in turn reacts with the sulfhydryl group of glutathione. Acetaminophen mercapturic acid is the final metabolite. If tissue glutathione stores are depleted as a result of fasting, intake of excessive doses of acetaminophen or through induction of CYP2E1 as a result of chronic intake of ethanol, the quinone interacts with nucleophilic sites of cellular macromolecules, such as proteins. Liver necrosis is the result. Regular intake of acetaminophen during fasting or chronic ethanol intake should be avoided. N-acetylcysteine is the antidote for acetaminophen poisoning. It reacts with the electrophile. A small amount of acetaminophen is reported to undergo deacetylation to the phase 1 metabolite p -aminophenol. www.freelivedoctor.com
  144. 144. N-ACETYLCYSTEINE FOR ACETAMINOPHEN TOXICITY www.freelivedoctor.com
  145. 145. CARCENOGENSIS www.freelivedoctor.com
  146. 146. N-Hydroxylation of AAF N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent www.freelivedoctor.com
  147. 147. Further Metabolism of N-HydroxyAAF Produces Cancer N-HydroxyAAF undergoes phase II metabolism to the ultimate carcingogen. The glucuronide pathway is also involved in carcinogenesis www.freelivedoctor.com
  148. 148. CYP1A1 Converts Benzopyrene to a Carcinogen www.freelivedoctor.com
  149. 149. Aflatoxin is Metabolized to a Carcinogenic Agent www.freelivedoctor.com
  150. 150. FACTORS AFFECTING DRUG METABOLISM www.freelivedoctor.com
  151. 151. ENZYME INDUCTION www.freelivedoctor.com
  152. 152. www.freelivedoctor.com
  153. 153. www.freelivedoctor.com
  154. 154. Factors Affecting Drug Metabolism <ul><li>Enzyme Induction - increased enzyme protein levels in the cell </li></ul><ul><ul><li>Phenobarbital type induction by many drugs </li></ul></ul><ul><ul><li>Polycyclic hydrocarbon type induction by polycyclic hydrocarbons such as 3,4-benzopyrene and 3-methylcholanthrene </li></ul></ul>www.freelivedoctor.com
  155. 155. AGE www.freelivedoctor.com
  156. 156. FACTORS AFFECTING DRUG METABOLISM <ul><li>Age </li></ul><ul><ul><li>Neonates </li></ul></ul><ul><ul><li>Children </li></ul></ul><ul><ul><li>Elderly </li></ul></ul>www.freelivedoctor.com
  157. 157. DIET www.freelivedoctor.com
  158. 158. FACTORS AFFECTING DRUG METABOLISM <ul><li>Diet </li></ul><ul><ul><li>Charcoal broiled foods (contain polycyclic hydrocarbons that increase certain enzyme protein in cells) </li></ul></ul><ul><ul><li>Grapefruit juice (the active component is the furancoumarin 6,7-dihydroxybergamottin which inhibits a certain a group of microsomal enzymes) </li></ul></ul>www.freelivedoctor.com
  159. 159. GENETIC VARIATION www.freelivedoctor.com
  160. 160. Some Enzymes That Exhibit Genetic Variation <ul><ul><li>Pseudocholinesterase </li></ul></ul><ul><ul><ul><li>typical enzyme </li></ul></ul></ul><ul><ul><ul><li>atypical enzyme </li></ul></ul></ul><ul><ul><li>N-Acetyltransferase (isoniazid is a substrate) </li></ul></ul><ul><ul><ul><li>fast acetylation </li></ul></ul></ul><ul><ul><ul><li>slow acetylation </li></ul></ul></ul><ul><ul><li>Cytochrome P450 2D6 </li></ul></ul><ul><ul><li>Cytochrome P450 2C19 </li></ul></ul><ul><ul><li>TMPT -Thiomethylpurinetransferase </li></ul></ul><ul><ul><li>Dihydropyrimidine Dehydrogenase </li></ul></ul>www.freelivedoctor.com
  161. 161. STATE OF HEALTH www.freelivedoctor.com
  162. 162. FACTORS AFFECTING DRUG METABOLISM <ul><li>State of health </li></ul><ul><ul><li>Hepatitis </li></ul></ul><ul><ul><li>Liver cancer </li></ul></ul><ul><ul><li>Cardiac insufficiency </li></ul></ul><ul><ul><li>Uremia </li></ul></ul><ul><ul><ul><li>degree of protein binding </li></ul></ul></ul>www.freelivedoctor.com
  163. 163. Changes In Drug Metabolism As A Consequence Of Hepatic Disease From Principles of Drug Action www.freelivedoctor.com
  164. 164. GENDER www.freelivedoctor.com
  165. 165. FACTORS AFFECTING DRUG METABOLISM <ul><li>Gender </li></ul><ul><ul><li>Most studies are performed in the rat. In general, male rats metabolize drugs faster than female rats </li></ul></ul>www.freelivedoctor.com
  166. 166. DEGREE OF PROTEIN BINDING www.freelivedoctor.com
  167. 167. FACTORS AFFECTING DRUG METABOLISM <ul><li>Degree of protein binding </li></ul><ul><ul><li>Conditions that displace bound drug from protein allows more of the drug to be accessible to the enzyme for which it serves as a substrate e.g. uremia, low plasma albumin </li></ul></ul>www.freelivedoctor.com
  168. 168. SPECIES VARIATION www.freelivedoctor.com
  169. 169. FACTORS AFFECTING DRUG METABOLISM <ul><li>Species variation </li></ul><ul><ul><li>Quantitative </li></ul></ul><ul><ul><li>Qualitative </li></ul></ul>www.freelivedoctor.com
  170. 170. Factors Affecting Drug Metabolism <ul><li>Species variation </li></ul><ul><ul><li>Human beings metabolize amphetamine by deamination; rats and dogs metabolize the drug by aromatic hydroxylation </li></ul></ul><ul><ul><li>Guinea pigs have very little sulfotransferase activity, humans have substantial activity </li></ul></ul><ul><ul><li>Guinea pigs do not N-hydroxylate substrates; mice, rabbits, dogs do </li></ul></ul><ul><ul><li>Hexobarbital is metabolized at different rates by different species </li></ul></ul>www.freelivedoctor.com
  171. 171. www.freelivedoctor.com
  172. 172. SUBSTRATE COMPETITION www.freelivedoctor.com
  173. 173. Factors Affecting Drug Metabolism <ul><li>Substrate competition </li></ul><ul><ul><li>Two or more drugs competing for the same enzyme can affect the metabolism of each other; the substrate for which the enzyme has the greater affinity would be preferentially metabolized </li></ul></ul>www.freelivedoctor.com