Successfully reported this slideshow.

pharmacokinetics

2,124 views

Published on

  • Be the first to comment

pharmacokinetics

  1. 1. DRUG METABOLISM
  2. 2. Transformation of Xenobiotics by Biological Systems
  3. 3. IMPLICATIONS FOR DRUG METABOLISM
  4. 4. IMPLICATIONS FOR DRUG METABOLISM1. Termination of drug action2. Activation of prodrug3. Bioactivation and toxication4. Carcinogenesis5. Tetratogenesis
  5. 5. Termination of Drug Action atropine tropic acid and tropinepropranolol → hydroxypropranolol (active) (active)
  6. 6. Termination of Drug ActionConversion of drug to active metabolite to activemetabolite to inactive metabolite
  7. 7. Activation of ProdrugL-dopa Dopamine
  8. 8. Inactive Terfenadine is Converted to its Active Metabolite Fexofenadine activation of prodrug terfenadine fexofenadine
  9. 9. Some Xenobiotics Are Metabolized to Carcinogenic Agents carcinogenesis • 3,4 Benzopyrene • Aflatoxin • N-Acetylaminoflluorene Metabolites of these agents interact with DNA
  10. 10. Small Amounts of Acetaminophen is Converted to the Reactive Metabolite N-Acetylbenzoquinoneimine bioactivationBioactivation of acetaminophen; under certain conditions, the electrophile N-acetylbenzoquinoneimine reacts with tissue macromolecules, causing liver necrosis.
  11. 11. Thalidomide is a Teratogen teratogensis– 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.
  12. 12. FACTORS AFFECTING DRUG METABOLISM
  13. 13. Factors Affecting Drug Metabolism• Age• Diet• Genetic Variation• State of Health• Gender• Degree of Protein Binding• Species Variation• Substrate Competition• Enzyme Induction• Route of Drug Administration
  14. 14. Factors Affecting Drug Metabolism• Route of drug administration – Oral versus systemic administration
  15. 15. Many Drugs Undergo First Pass Metabolism Upon Oral Administration• Oral administration• Drug travels from gut to portal vein to liver• Vigorous metabolism occurs in the liver. Little drug gets to the systemic circulation• The wall of the small intestine also contributes to first pass metabolism
  16. 16. ORGAN SITES OF DRUG METABOLISM
  17. 17. Organ Sites of Drug Metabolism• Liver• Small intestine• Kidney• Skin• Lungs• Plasma• All organs of the body
  18. 18. CELLULAR SITES OF DRUG METABOLISM
  19. 19. Cellular Sites Of Drug Metabolism• Cytosol• Mitochondria• Lysosomes• Smooth endoplasmic reticulum (microsomes)
  20. 20. KINETICS OF DRUG METABOLISM
  21. 21. Velocity Of Metabolism Of A Drug 80 70 60 (ng/g tissue/min)Velocity 50 40 30 20 10 0 0 10 20 30 40 50 60 70 [Drug] mM D:summer1Kmx1.pzm
  22. 22. Velocity Of Metabolism Of A Drug 80 70 60 zero order metabolism (ng/g tissue/min)Velocity 50 40 30 20 first order metabolism 10 0 0 5 10 15 20 25 30 35 40 45 50 55 60 [Drug] mM Kmx2.pzm
  23. 23. First Order MetabolismA drug may be given in doses that produce bloodconcentrations less than the Km of the enyzme for the drug. v = Vmax [C] Km + [C] When Km >>> [C], then v = Vmax [C] , and v α [C] KmMetabolism of the drug is a first order process. A constantfraction of the remaining drug is metabolized per unit time.Most drugs are given at concentrations smaller than the Kmof the enzymes of their metabolism.
  24. 24. Velocity Of Metabolism Of A Drug 80 70 60 zero order metabolism (ng/g tissue/min)Velocity 50 40 30 20 first order metabolism 10 0 0 5 10 15 20 25 30 35 40 45 50 55 60 [Drug] mM Kmx2.pzm
  25. 25. Zero Order MetabolismA drug may be given in doses that produce blood concentrationsgreater than the Km of the enyzme for the drug. v = Vmax [C] K m + [C] When [C] >>> Km, then v = Vmax [C] , and v = Vmax [C] 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.
  26. 26. Velocity Of Metabolism Of A Drug 80 70 60 zero order metabolism (ng/g tissue/min)Velocity 50 40 30 20 first order metabolism 10 0 0 5 10 15 20 25 30 35 40 45 50 55 60 [Drug] mM Kmx2.pzm
  27. 27. Velocity Of Metabolism Of Three Drugs By The Same Enzyme 70 60 (ng/g tissue/min ) 50Velocity Drug A 40 Drug B 30 Drug C 20 10 0 0 10 20 30 40 50 60 70 80 90 [Drug] mM
  28. 28. PHASES OF DRUG METABOLISM
  29. 29. Phase I MetabolismPolar groups are exposed on or introduced to a moleculeR ROH R RCOOHR RSH R RNH2
  30. 30. Phase I Reactions OXIDATION REDUCTIONHYDROLYSIS
  31. 31. Phase II MetabolismA molecule endogenous to the body donates a portionof itself to the foreign moleculeD+ENDOX DX+ENDO
  32. 32. Patterns of Drug Metabolism • Parent molecule → Phase 1 metabolism • Phase 1 metabolite → Phase 2 metabolism • Parent molecule → Phase 2 metabolism • Phase 2 metabolite → Phase 1 metabolismSome drugs are not metabolized, for example, gallamineand decamethonium. Atracurium undergoes spontaneoushydrolysis.
  33. 33. PHASE I METABOLIC PATHWAYS
  34. 34. Microsomal Oxidation
  35. 35. Preparation Of Microsomes
  36. 36. Cytochrome P450fp = NADPH cytochrome P450 reductase, or NADH cytochrome b5reductase
  37. 37. Oxidation Of Drugs By Cytochrome P450
  38. 38. Oxidation Of Drugs By Cytochrome P450
  39. 39. Aliphatic Oxidation
  40. 40. Aromatic Hydroxylation (1)acetanilid p-hydroxyacetanilid
  41. 41. Aromatic Hydroxylation (2)
  42. 42. N-Dealkylation
  43. 43. O-Dealkylation
  44. 44. S-Demethylation
  45. 45. Oxidative Deamination
  46. 46. S-Oxidation
  47. 47. N-Oxidation
  48. 48. N-Hydroxylation
  49. 49. N-Hydroxylation of AAFN-Hydroxylation of AAF is the first metabolic step towardsthe development of a carcinogenic agent
  50. 50. Oxidative Dehalogenation
  51. 51. Desulfuration
  52. 52. Desulfuration
  53. 53. ISOENZMYES OF CYTOCHROME P450CYP1A1 CYP2D6CYP1A2 CYP2AE1CYP2A6 CYP3A4CYP2B_ CYP3A5CYP2C9 CYP3A7CYP2C19 CYP4A_
  54. 54. Cytochrome P450 3A4 (CYP3A4)
  55. 55. CYP3A4• CYP3A4 is responsible for metabolism of 60% of all drugs• It comprises approximately 28% of hepatic cytochrome P450• Metabolizes terfenadine• Ingestion of grapefruit juice reduces expression of this enzyme• Inhibited by some regularly used drugs
  56. 56. Some Drugs That Inhibit CYP3A4• Macrolide antibiotics – Erythromycin – Clarithromycin – Other such agents• Antifungal agents – Ketoconazole – Itraconazole – Other such agents• HIV protease inhibitors
  57. 57. CYP3A4• Ketoconazole and terfenadine can produce a drug interaction with fatal consequences.
  58. 58. CONVERSION OF TERFENADINE TO FEXOFENADINE O2, NADPH CYP3A4
  59. 59. AN INGREDIENT IN GRAPEFRUIT JUICE INHIBITS CYP3A4
  60. 60. Grapefruit Juice Increases Felodipine Oral Availability inHumans by Decreasing Intestinal CYP3A Protein Expression Hours J.Clin. Invest. 99:10, p.2545-53, 1997
  61. 61. 6,7, - Dihydroxybergamottin
  62. 62. Grapefruit Juice Consumption Blocks Terfenadine Metabolism to Fexofenadine X
  63. 63. CYP3A4 And P-Glycoprotein• P-Glycoprotein and CYP3A4 control oral bioavailability of many drugs• P-Glycoprotein and CYP3A4 share many substrates and inhibitors
  64. 64. CYP2D6 is an Enzyme with Polymorphisms• Approximately 70 nucleotide polymorphisms are known• Four phenotype subpopulations of metabolizers* – Poor metabolizers (PM) – Intermediate metabolizers (IM) – Extensive metabolizers (EM) – Ultrarapid metabolizers (UM)• Variations according to racial background• More than 65 commonly used drugs are substrates• Codeine is a well known substrate * The Pharmacological Basis of Therapeutics
  65. 65. Codeine is a Substrate of CYP2D6 -CH3 (methyl morphine)Consider the variation in codeine’s metabolism amongPM, IM, EM, UM individuals
  66. 66. CYP2C9• Metabolizes some 16 commonly used drugs• Warfarin and phenytoin are among the substrates• Two allelic variants are known: metabolizes substrates 5% to 12% of the wild type enzyme – Warfarin clearance is greatly reduced in individuals possessing the allelic variants• Dose adjustments are required for drugs in individuals who have the mutant enzymes
  67. 67. CYP2C19• S-mephenytoin is a substrate – (4-hydroxylation at the phenyl ring)• As much as eight allelic variants identified – All are nonfunctional proteins• Poor metabolizers of S-mephenytoin lack 4-hydroxylase activity, but N-demethylation to nirvanol is an alternative but slow metabolic pathway – Dose adjustments must be made for poor metabolizers of S-mephenytoin and for other drugs that are substrates for this enzyme
  68. 68. CYP1A1• Polycyclic hydrocarbons are among its substrates• Inducers include – Polycyclic hydrocarbons such as 3,4,-benzopyrene, 3-methylcholanthrene, etc. – Charcoal broiled foods (polycyclic hydrocarbons)
  69. 69. CIMETIDINE Inhibits CYP450 Metabolism Of Many Drugs Warfarin Triazolam Phenytoin Chlordiazepoxide Metoprolol Carbamazepine Labetalol Quinidine Quinidine Ethanol Caffeine Tricyclic antidepressants Lidocaine Metronidazole Theophylline Calcium channel Alprazolam blockers Diazepam Diazepam Flurazepam Sulfonylureas
  70. 70. NONMICROSOMAL OXIDATIONS ALCOHOL DEHYDROGENATION ALDEHYDE DEHYDROGENATION XANTHINE OXIDATION DIAMINE OXIDATION MONOAMINE OXIDATION
  71. 71. Nonmicrosomal OxidationsAlcohol dehydrogenation is conducted by the enzymealcohol dehydrogenase (cytosolic)Aldehyde dehydrogenation is conducted by the enzymealdehyde dehydrogenase (cytosol and mitochondria)Xanthine oxidation is conducted by the cytosolic enzymexanthine oxidase.Diamine oxidase (cytosolic) oxidizes histamine anddiamines such as cadaverine and putrescine.Monoamine oxidation is conducted by mitochondrialmonoamine oxidase (norepinephrine, epinephrine,dopamine and serotonin are endogenous substrates.
  72. 72. Monoamine Oxidase Metabolism of Serotonin
  73. 73. Some Popular Substrates of Monoamine Oxidase• Serotonin• Epinephrine• Norepinephrine• Dopamine• Tyramine (found in certain foods)
  74. 74. Diamine Oxidasecadaverine
  75. 75. Alcohol Dehydrogenase• A soluble enzyme, found almost exclusively in the parenchymal cells of the liver• Converts ethanol to acetaldehyde• Converts methanol to formaldehyde• Converts ethylene glycol to its respective aldehyde metabolites• Is inhibited by pyrazole
  76. 76. Alcohol DehydrogenaseCH3CH2OH + NAD+ → CH3CHO + NADH + H+ ethanol acetaldehyde
  77. 77. Aldehyde DehydrogenaseCH3CHO + NAD+ → CH3COOH + NADH + H+acetaldehyde acetate
  78. 78. XANTHINE OXIDASE
  79. 79. Xanthine Oxidase
  80. 80. REDUCTION
  81. 81. NITRO REDUCTION Nitro Reduction RNO2 RNH2 MICROSOMES AND CYTOSOLMicrosomes and cytosol
  82. 82. Nitro Reduction
  83. 83. AZO REDUCTION Azo ReductionRN=NR RNH2 + RNH2Microsomes and cytosolMICROSOMES AND CYTOSOL
  84. 84. Azo ReductionMicrosomes and cytosol
  85. 85. Alcohol DehydrogenationCytosol
  86. 86. DIHYDROPYRIMIDINE DEHYDROGENASE5-Fluorouracil DPYD 5-Fluoro-5,6-dihydrouracil• DPYD – Inactivates 5-fluorouracil by ring reduction – Inherited deficiency of this enzyme leads to 5-fluorouracil toxicity – Enzyme deficiency can be detected by enzymatic or molecular assays using white blood cells 5-fluorouracil
  87. 87. HYDROLYSIS
  88. 88. Amide HydrolysisAMIDE HYDROLYSISRCONRR" RCOOH+ HNRR"Microsomes and cytosolMICROSOMES AND CYTOSOL
  89. 89. ESTER HYDROLYSIS Ester HydrolysisRCOOR RCOOH + ROHMICROSOMES AND CYTOSOLMicrosomes and cytosol
  90. 90. Ester Hydrolysis EnalapritMicrosomes and cytosol
  91. 91. EPOXIDE HYDROLASE
  92. 92. Epoxide Hydrolase• A microsomal enzyme
  93. 93. Epoxide Hydrolase
  94. 94. PHASE II METABOLIC PATHWAYS
  95. 95. PHASE 2 METABOLISMA molecule endogenous to the body donates a portionof itself to the foreign moleculeD+ENDOX DX+ENDO
  96. 96. PHASE II REACTIONS Glucuronidation Sulfate Conjugation Acetylation Glycine Conjugation Methylation Transulfuration Glutathione ConjugationMercapturic Acid Synthesis
  97. 97. GLUCURONIDATION
  98. 98. Uridine-5’-α-D-glucuronic AcidThe microsomal enzyme glucuronyl transferase conducts thedonation of glucuronic acid from the endogenously synthesizedUDPGA to various substrates to form glucuronide conjugates.Examples of such substrates are morphine and acetaminophen.
  99. 99. UDP-α-D-Glucuronsyltransferase• Is also called glucuronyl transferase• A microsomal enzyme• Substrates are called aglycones• Conducts phase 2 metabolic reactions• Products are called glucuronides• Glucuronides formed – RN-G; RO-G; RCOO-G; RS-G; RC-G• Bilirubin is an endogenous substrate• Induced by phenobarbital
  100. 100. Glucuronidation of Benzoic AcidUGT= UDP-α-D-Glucuronsyltransferase
  101. 101. Glucuronidation of Aniline
  102. 102. Glucuronidation of p-Hydroxyacetanilid
  103. 103. Morphine MetabolismMorphine → Morphine -6-glucuronide (active metabolite)Morphine → Morphine -3-glucuronide (inactive metabolite) A small amount of morphine undergoes N-demethylation
  104. 104. Morphine MetabolismMorphine -3-glucuronide is the major metabolite
  105. 105. Induction Of UDP-α-D-Glucuronyl Transferase• Induced by phenobarbital• Induced by 3-methylcholanthrene
  106. 106. Glucuronidation in the Cat• The cat can glucuronidate bilirubin but cannot glucuronidate phenolic compounds such as phenol and napthol
  107. 107. SULFATE CONJUGATION
  108. 108. 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
  109. 109. 3’-Phosphoadenosine-5’-phosphosulfate (PAPS)The cytosolic enzyme sulfotransferase conducts the donation ofsulfate from the endogenously synthesized PAPS to varioussubstrates to form sulfate conjugates. An example of such substrateis acetaminophen.
  110. 110. Sulfate Conjugation of p-HydroxyacetanilidPAP: 3’-phosphoadenosine- 5’-phosphate
  111. 111. MINOXIDIL METABOLISMMINOXIDIL MINOXIDIL N-O-SULFATE(inactive) (active metabolite) MINOXIDIL N-O-GLUCURONIDE (inactive metabolite)
  112. 112. Species Differences in Sulfate Conjugation• Some species are deficient in the sulfate conjugation pathway – Pig – Opposum
  113. 113. N-ACETYLATION
  114. 114. N-Acetyltransferase• 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
  115. 115. Acetyl CoAVarious acetylases, for examples, choline acetylase and N-acetyltransferase, all soluble enzymes, conduct the transfer of the acetylgroup of acetyl CoA to various substrates. For example, N-acetylationof isoniazid. Genetic polyporphism occurs with N-acetyltransferase.
  116. 116. N-Acetyltransferase
  117. 117. N-Acetyltransferase• The dog cannot acetylate aromatic amino compounds because it lacks the appropriate isoenzyme of NAT
  118. 118. SUGAR CONJUGATION
  119. 119. Conversion of 6-Mercaptopurine to a Nucleotide
  120. 120. METHYLATION
  121. 121. S-AdenosylmethionineCytosolic enzymes such as catechol-O-methyl transferase (COMT) andphenylethanolamine-N-methyl transferase (PNMT) conducts thedonation of the methyl group from the endogenously synthesized SAMto various substrates to form methylated conjugates. Norepinephrine isN-methylated by PNMT to form epinephrine. Norepinephrine,epinephrine, dopamine, and L-DOPA are O-methylated by COMT.
  122. 122. Methyltransferases• A family of soluble enzymes that conducts – N-methylation; N-CH3 – O-methylation; O-CH3 – S-methylation; S-CH3• S-adenosylmethionine (SAM)is the endogenous donor molecule. It is demethylated to S-adenosylhomocysteine
  123. 123. N-MethyltransferasesPNMT- Phenylethanolamine-N-methyltransferase PNMTNorepinephrine Epinephrine SAM
  124. 124. O-Methylation Of CatecholaminesCOMT- catechol-O-methyltransferase
  125. 125. O-Methylation of NorepinephrineCOMT- catechol-O-methyltransferase
  126. 126. S-Methylation of 6-MercaptopurineTPMT - thiopurinemethyltransferase; some individuals aredeficient in this enzyme that is critically important for themetabolism of this agent
  127. 127. METABOLISM OF MERCAPTOPURINE (1) TMPT6-Mercaptopurine 6-Methylmercaptopurine• TMPT -Thiomethylpurinetransferase – Conducts S-methylation of the substrate – Found in RBC’s – Isoforms exist • active enzyme • inactive enzyme
  128. 128. AMINO ACID CONJUGATION
  129. 129. AMINO ACID CONJUGATION (mitochondria)
  130. 130. Multiple Metabolic Pathways Exist for Aspirin’s MetabolismHydolysis of aspirin produces salicyclic acid, asseen in the next slide
  131. 131. Salicyluric Acid is the Glycine Conjugate of AspirinSalicyluric acid, the glycine conjugate of salicyclic acid, is the mainmetabolite of aspirin. Approximately 76% of aspirin is metabolizedthrough amino acid conjugation.
  132. 132. Acetyl Salicylic Acid (Aspirin) Metabolism• Salicylic acid the hydrolytic product of acetyl salicylic acid. Salicylic acid is further metabolized• Salicyl uric acid is the glycine conjugate and the main metabolite of aspirin. About 75% of aspirin is metabolized by this pathway• Other metabolites of aspirin – the acyl glucuronide conjugate of salicylic acid (salicylic acid glucuronide) – the phenol glucuronide conjugate of salicylic acid (salicyl phenol glucuronide) – the ring hydroxylated product of salicylic acid (gentisic acid) – the ring hydroxylated product of the glycine conjugate (gentisuric acid
  133. 133. TRANSULFURATION
  134. 134. TRANSULFURATION
  135. 135. GLUTATHIONE CONJUGATION
  136. 136. DRUG INTERACTION WITH GLUTATHIONE mercapturate metabolite of drug
  137. 137. 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”
  138. 138. ACETAMINOPHEN METABOLISM
  139. 139. Bioactivation of Acetaminophen
  140. 140. ACETAMINOPHEN AND ITS PHASE II METABOLITESThe sulfate and glucuronide conjugates of acetaminophen are the majormetabolites. High doses of acetaminophen can exhaust the metabolic pathwaysthat produce these conjugates, allowing more of the parent drug to undergo thephase I metabolic pathway which is involved in bioactivation and toxication.
  141. 141. ACETAMINOPHEN AND ITS PHASE I METABOLITES
  142. 142. ACETAMINOPHEN AND ITS PHASE I METABOLITES- pt2The minor metabolite (4% of acetaminophen), N-hydroxyacetaminophen,is always produced by microsomal cytochrome P450. It rearranges tothe electrophile N-acetylbenzoquinoneimine, which in turn reacts withthe sulfhydryl group of glutathione. Acetaminophen mercapturic acid isthe final metabolite. If tissue glutathione stores are depleted as a resultof fasting, intake of excessive doses of acetaminophen or throughinduction of CYP2E1 as a result of chronic intake of ethanol, thequinone interacts with nucleophilic sites of cellular macromolecules,such as proteins. Liver necrosis is the result. Regular intake ofacetaminophen during fasting or chronic ethanol intake should beavoided. N-acetylcysteine is the antidote for acetaminophen poisoning.It reacts with the electrophile. A small amount of acetaminophen isreported to undergo deacetylation to the phase 1 metabolite p-aminophenol.
  143. 143. N-ACETYLCYSTEINE FOR ACETAMINOPHEN TOXICITY
  144. 144. CARCENOGENSIS
  145. 145. N-Hydroxylation of AAFN-Hydroxylation of AAF is the first metabolic step towardsthe development of a carcinogenic agent
  146. 146. Further Metabolism of N-HydroxyAAF Produces CancerN-HydroxyAAF undergoes phase II metabolism to theultimate carcingogen. The glucuronide pathway is alsoinvolved in carcinogenesis
  147. 147. CYP1A1 Converts Benzopyrene to a Carcinogen
  148. 148. Aflatoxin is Metabolized to a Carcinogenic Agent
  149. 149. FACTORS AFFECTING DRUG METABOLISM
  150. 150. ENZYME INDUCTION
  151. 151. CORRELATION BETWEEN SLEEPING TIME AND PLASMAT1/2 IN CHRONIC PENTOBARBITAL PRETREATED RABBITS
  152. 152. Factors Affecting Drug Metabolism• Enzyme Induction - increased enzyme protein levels in the cell – Phenobarbital type induction by many drugs – Polycyclic hydrocarbon type induction by polycyclic hydrocarbons such as 3,4-benzopyrene and 3-methylcholanthrene
  153. 153. AGE
  154. 154. FACTORS AFFECTING DRUG METABOLISM• Age – Neonates – Children – Elderly
  155. 155. DIET
  156. 156. FACTORS AFFECTING DRUG METABOLISM• Diet – Charcoal broiled foods (contain polycyclic hydrocarbons that increase certain enzyme protein in cells) – Grapefruit juice (the active component is the furancoumarin 6,7-dihydroxybergamottin which inhibits a certain a group of microsomal enzymes)
  157. 157. GENETIC VARIATION
  158. 158. Some Enzymes That Exhibit Genetic Variation– Pseudocholinesterase • typical enzyme • atypical enzyme– N-Acetyltransferase (isoniazid is a substrate) • fast acetylation • slow acetylation– Cytochrome P450 2D6– Cytochrome P450 2C19– TMPT -Thiomethylpurinetransferase– Dihydropyrimidine Dehydrogenase
  159. 159. STATE OF HEALTH
  160. 160. FACTORS AFFECTING DRUG METABOLISM• State of health – Hepatitis – Liver cancer – Cardiac insufficiency – Uremia • degree of protein binding
  161. 161. Changes In Drug Metabolism As A Consequence Of Hepatic Disease From Principles of Drug Action
  162. 162. GENDER
  163. 163. FACTORS AFFECTING DRUG METABOLISM• Gender – Most studies are performed in the rat. In general, male rats metabolize drugs faster than female rats
  164. 164. DEGREE OF PROTEIN BINDING
  165. 165. FACTORS AFFECTING DRUG METABOLISM• Degree of protein binding – 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
  166. 166. SPECIES VARIATION
  167. 167. FACTORS AFFECTING DRUG METABOLISM• Species variation – Quantitative – Qualitative
  168. 168. Factors Affecting Drug Metabolism• Species variation – Human beings metabolize amphetamine by deamination; rats and dogs metabolize the drug by aromatic hydroxylation – Guinea pigs have very little sulfotransferase activity, humans have substantial activity – Guinea pigs do not N-hydroxylate substrates; mice, rabbits, dogs do – Hexobarbital is metabolized at different rates by different species
  169. 169. SUBSTRATE COMPETITION
  170. 170. Factors Affecting Drug Metabolism• Substrate competition – 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

×