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pharmacokinetics

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  • 1. DRUG METABOLISM
  • 2. Transformation of Xenobiotics by Biological Systems
  • 3. IMPLICATIONS FOR DRUG METABOLISM
  • 4. IMPLICATIONS FOR DRUG METABOLISM1. Termination of drug action2. Activation of prodrug3. Bioactivation and toxication4. Carcinogenesis5. Tetratogenesis
  • 5. Termination of Drug Action atropine tropic acid and tropinepropranolol → hydroxypropranolol (active) (active)
  • 6. Termination of Drug ActionConversion of drug to active metabolite to activemetabolite to inactive metabolite
  • 7. Activation of ProdrugL-dopa Dopamine
  • 8. Inactive Terfenadine is Converted to its Active Metabolite Fexofenadine activation of prodrug terfenadine fexofenadine
  • 9. Some Xenobiotics Are Metabolized to Carcinogenic Agents carcinogenesis • 3,4 Benzopyrene • Aflatoxin • N-Acetylaminoflluorene Metabolites of these agents interact with DNA
  • 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. 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. FACTORS AFFECTING DRUG METABOLISM
  • 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. Factors Affecting Drug Metabolism• Route of drug administration – Oral versus systemic administration
  • 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. ORGAN SITES OF DRUG METABOLISM
  • 17. Organ Sites of Drug Metabolism• Liver• Small intestine• Kidney• Skin• Lungs• Plasma• All organs of the body
  • 18. CELLULAR SITES OF DRUG METABOLISM
  • 19. Cellular Sites Of Drug Metabolism• Cytosol• Mitochondria• Lysosomes• Smooth endoplasmic reticulum (microsomes)
  • 20. KINETICS OF DRUG METABOLISM
  • 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. 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. 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. 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. 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. 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. 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. PHASES OF DRUG METABOLISM
  • 29. Phase I MetabolismPolar groups are exposed on or introduced to a moleculeR ROH R RCOOHR RSH R RNH2
  • 30. Phase I Reactions OXIDATION REDUCTIONHYDROLYSIS
  • 31. Phase II MetabolismA molecule endogenous to the body donates a portionof itself to the foreign moleculeD+ENDOX DX+ENDO
  • 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. PHASE I METABOLIC PATHWAYS
  • 34. Microsomal Oxidation
  • 35. Preparation Of Microsomes
  • 36. Cytochrome P450fp = NADPH cytochrome P450 reductase, or NADH cytochrome b5reductase
  • 37. Oxidation Of Drugs By Cytochrome P450
  • 38. Oxidation Of Drugs By Cytochrome P450
  • 39. Aliphatic Oxidation
  • 40. Aromatic Hydroxylation (1)acetanilid p-hydroxyacetanilid
  • 41. Aromatic Hydroxylation (2)
  • 42. N-Dealkylation
  • 43. O-Dealkylation
  • 44. S-Demethylation
  • 45. Oxidative Deamination
  • 46. S-Oxidation
  • 47. N-Oxidation
  • 48. N-Hydroxylation
  • 49. N-Hydroxylation of AAFN-Hydroxylation of AAF is the first metabolic step towardsthe development of a carcinogenic agent
  • 50. Oxidative Dehalogenation
  • 51. Desulfuration
  • 52. Desulfuration
  • 53. ISOENZMYES OF CYTOCHROME P450CYP1A1 CYP2D6CYP1A2 CYP2AE1CYP2A6 CYP3A4CYP2B_ CYP3A5CYP2C9 CYP3A7CYP2C19 CYP4A_
  • 54. Cytochrome P450 3A4 (CYP3A4)
  • 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. Some Drugs That Inhibit CYP3A4• Macrolide antibiotics – Erythromycin – Clarithromycin – Other such agents• Antifungal agents – Ketoconazole – Itraconazole – Other such agents• HIV protease inhibitors
  • 57. CYP3A4• Ketoconazole and terfenadine can produce a drug interaction with fatal consequences.
  • 58. CONVERSION OF TERFENADINE TO FEXOFENADINE O2, NADPH CYP3A4
  • 59. AN INGREDIENT IN GRAPEFRUIT JUICE INHIBITS CYP3A4
  • 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. 6,7, - Dihydroxybergamottin
  • 62. Grapefruit Juice Consumption Blocks Terfenadine Metabolism to Fexofenadine X
  • 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. 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. Codeine is a Substrate of CYP2D6 -CH3 (methyl morphine)Consider the variation in codeine’s metabolism amongPM, IM, EM, UM individuals
  • 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. 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. 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. 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. NONMICROSOMAL OXIDATIONS ALCOHOL DEHYDROGENATION ALDEHYDE DEHYDROGENATION XANTHINE OXIDATION DIAMINE OXIDATION MONOAMINE OXIDATION
  • 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. Monoamine Oxidase Metabolism of Serotonin
  • 73. Some Popular Substrates of Monoamine Oxidase• Serotonin• Epinephrine• Norepinephrine• Dopamine• Tyramine (found in certain foods)
  • 74. Diamine Oxidasecadaverine
  • 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. Alcohol DehydrogenaseCH3CH2OH + NAD+ → CH3CHO + NADH + H+ ethanol acetaldehyde
  • 77. Aldehyde DehydrogenaseCH3CHO + NAD+ → CH3COOH + NADH + H+acetaldehyde acetate
  • 78. XANTHINE OXIDASE
  • 79. Xanthine Oxidase
  • 80. REDUCTION
  • 81. NITRO REDUCTION Nitro Reduction RNO2 RNH2 MICROSOMES AND CYTOSOLMicrosomes and cytosol
  • 82. Nitro Reduction
  • 83. AZO REDUCTION Azo ReductionRN=NR RNH2 + RNH2Microsomes and cytosolMICROSOMES AND CYTOSOL
  • 84. Azo ReductionMicrosomes and cytosol
  • 85. Alcohol DehydrogenationCytosol
  • 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. HYDROLYSIS
  • 88. Amide HydrolysisAMIDE HYDROLYSISRCONRR" RCOOH+ HNRR"Microsomes and cytosolMICROSOMES AND CYTOSOL
  • 89. ESTER HYDROLYSIS Ester HydrolysisRCOOR RCOOH + ROHMICROSOMES AND CYTOSOLMicrosomes and cytosol
  • 90. Ester Hydrolysis EnalapritMicrosomes and cytosol
  • 91. EPOXIDE HYDROLASE
  • 92. Epoxide Hydrolase• A microsomal enzyme
  • 93. Epoxide Hydrolase
  • 94. PHASE II METABOLIC PATHWAYS
  • 95. PHASE 2 METABOLISMA molecule endogenous to the body donates a portionof itself to the foreign moleculeD+ENDOX DX+ENDO
  • 96. PHASE II REACTIONS Glucuronidation Sulfate Conjugation Acetylation Glycine Conjugation Methylation Transulfuration Glutathione ConjugationMercapturic Acid Synthesis
  • 97. GLUCURONIDATION
  • 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. 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. Glucuronidation of Benzoic AcidUGT= UDP-α-D-Glucuronsyltransferase
  • 101. Glucuronidation of Aniline
  • 102. Glucuronidation of p-Hydroxyacetanilid
  • 103. Morphine MetabolismMorphine → Morphine -6-glucuronide (active metabolite)Morphine → Morphine -3-glucuronide (inactive metabolite) A small amount of morphine undergoes N-demethylation
  • 104. Morphine MetabolismMorphine -3-glucuronide is the major metabolite
  • 105. Induction Of UDP-α-D-Glucuronyl Transferase• Induced by phenobarbital• Induced by 3-methylcholanthrene
  • 106. Glucuronidation in the Cat• The cat can glucuronidate bilirubin but cannot glucuronidate phenolic compounds such as phenol and napthol
  • 107. SULFATE CONJUGATION
  • 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. 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. Sulfate Conjugation of p-HydroxyacetanilidPAP: 3’-phosphoadenosine- 5’-phosphate
  • 111. MINOXIDIL METABOLISMMINOXIDIL MINOXIDIL N-O-SULFATE(inactive) (active metabolite) MINOXIDIL N-O-GLUCURONIDE (inactive metabolite)
  • 112. Species Differences in Sulfate Conjugation• Some species are deficient in the sulfate conjugation pathway – Pig – Opposum
  • 113. N-ACETYLATION
  • 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. 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. N-Acetyltransferase
  • 117. N-Acetyltransferase• The dog cannot acetylate aromatic amino compounds because it lacks the appropriate isoenzyme of NAT
  • 118. SUGAR CONJUGATION
  • 119. Conversion of 6-Mercaptopurine to a Nucleotide
  • 120. METHYLATION
  • 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. 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. N-MethyltransferasesPNMT- Phenylethanolamine-N-methyltransferase PNMTNorepinephrine Epinephrine SAM
  • 124. O-Methylation Of CatecholaminesCOMT- catechol-O-methyltransferase
  • 125. O-Methylation of NorepinephrineCOMT- catechol-O-methyltransferase
  • 126. S-Methylation of 6-MercaptopurineTPMT - thiopurinemethyltransferase; some individuals aredeficient in this enzyme that is critically important for themetabolism of this agent
  • 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. AMINO ACID CONJUGATION
  • 129. AMINO ACID CONJUGATION (mitochondria)
  • 130. Multiple Metabolic Pathways Exist for Aspirin’s MetabolismHydolysis of aspirin produces salicyclic acid, asseen in the next slide
  • 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. 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. TRANSULFURATION
  • 134. TRANSULFURATION
  • 135. GLUTATHIONE CONJUGATION
  • 136. DRUG INTERACTION WITH GLUTATHIONE mercapturate metabolite of drug
  • 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. ACETAMINOPHEN METABOLISM
  • 139. Bioactivation of Acetaminophen
  • 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. ACETAMINOPHEN AND ITS PHASE I METABOLITES
  • 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. N-ACETYLCYSTEINE FOR ACETAMINOPHEN TOXICITY
  • 144. CARCENOGENSIS
  • 145. N-Hydroxylation of AAFN-Hydroxylation of AAF is the first metabolic step towardsthe development of a carcinogenic agent
  • 146. Further Metabolism of N-HydroxyAAF Produces CancerN-HydroxyAAF undergoes phase II metabolism to theultimate carcingogen. The glucuronide pathway is alsoinvolved in carcinogenesis
  • 147. CYP1A1 Converts Benzopyrene to a Carcinogen
  • 148. Aflatoxin is Metabolized to a Carcinogenic Agent
  • 149. FACTORS AFFECTING DRUG METABOLISM
  • 150. ENZYME INDUCTION
  • 151. CORRELATION BETWEEN SLEEPING TIME AND PLASMAT1/2 IN CHRONIC PENTOBARBITAL PRETREATED RABBITS
  • 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. AGE
  • 154. FACTORS AFFECTING DRUG METABOLISM• Age – Neonates – Children – Elderly
  • 155. DIET
  • 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. GENETIC VARIATION
  • 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. STATE OF HEALTH
  • 160. FACTORS AFFECTING DRUG METABOLISM• State of health – Hepatitis – Liver cancer – Cardiac insufficiency – Uremia • degree of protein binding
  • 161. Changes In Drug Metabolism As A Consequence Of Hepatic Disease From Principles of Drug Action
  • 162. GENDER
  • 163. FACTORS AFFECTING DRUG METABOLISM• Gender – Most studies are performed in the rat. In general, male rats metabolize drugs faster than female rats
  • 164. DEGREE OF PROTEIN BINDING
  • 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. SPECIES VARIATION
  • 167. FACTORS AFFECTING DRUG METABOLISM• Species variation – Quantitative – Qualitative
  • 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. SUBSTRATE COMPETITION
  • 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