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Drug metabolism
 

Drug metabolism

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    Drug metabolism Drug metabolism Presentation Transcript

    • DRUG METABOLISM www.freelivedoctor.com
    • Transformation of Xenobiotics by Biological Systems www.freelivedoctor.com
    • IMPLICATIONS FOR DRUG METABOLISM www.freelivedoctor.com
    • IMPLICATIONS FOR DRUG METABOLISM 1. Termination of drug action 2. Activation of prodrug 3. Bioactivation and toxication 4. Carcinogenesis 5. Tetratogenesis www.freelivedoctor.com
    • Termination of Drug Action www.freelivedoctor.com tropic acid and tropine atropine propranolol  hydroxypropranolol (active) (active)
    • Termination of Drug Action Conversion of drug to active metabolite to active metabolite to inactive metabolite www.freelivedoctor.com
    • Activation of Prodrug www.freelivedoctor.com Dopamine L-dopa
    • Inactive Terfenadine is Converted to its Active Metabolite Fexofenadine terfenadine fexofenadine activation of prodrug www.freelivedoctor.com
    • Some Xenobiotics Are Metabolized to Carcinogenic Agents
      • 3,4 Benzopyrene
      • Aflatoxin
      • N-Acetylaminoflluorene
      Metabolites of these agents interact with DNA carcinogenesis www.freelivedoctor.com
    • 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
    • Thalidomide is a Teratogen
        • 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.
      teratogensis www.freelivedoctor.com
    • FACTORS AFFECTING DRUG METABOLISM www.freelivedoctor.com
    • 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
      www.freelivedoctor.com
    • Factors Affecting Drug Metabolism
      • Route of drug administration
        • Oral versus systemic administration
      www.freelivedoctor.com
    • 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
      www.freelivedoctor.com
    • ORGAN SITES OF DRUG METABOLISM www.freelivedoctor.com
    • Organ Sites of Drug Metabolism
      • Liver
      • Small intestine
      • Kidney
      • Skin
      • Lungs
      • Plasma
      • All organs of the body
      www.freelivedoctor.com
    • CELLULAR SITES OF DRUG METABOLISM www.freelivedoctor.com
    • Cellular Sites Of Drug Metabolism
      • Cytosol
      • Mitochondria
      • Lysosomes
      • Smooth endoplasmic reticulum (microsomes)
      www.freelivedoctor.com
    • KINETICS OF DRUG METABOLISM www.freelivedoctor.com
    • Velocity Of Metabolism Of A Drug D:summer1Kmx1.pzm www.freelivedoctor.com
    • Velocity Of Metabolism Of A Drug Kmx2.pzm www.freelivedoctor.com
    • 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
    • Velocity Of Metabolism Of A Drug Kmx2.pzm www.freelivedoctor.com
    • 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
    • Velocity Of Metabolism Of A Drug Kmx2.pzm www.freelivedoctor.com
    • Velocity Of Metabolism Of Three Drugs By The Same Enzyme www.freelivedoctor.com
    • PHASES OF DRUG METABOLISM www.freelivedoctor.com
    • 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
    • Phase I Reactions OXIDATION REDUCTION HYDROLYSIS www.freelivedoctor.com
    • 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
    • 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 metabolism
      Some drugs are not metabolized, for example, gallamine and decamethonium. Atracurium undergoes spontaneous hydrolysis. www.freelivedoctor.com
    • PHASE I METABOLIC PATHWAYS www.freelivedoctor.com
    • Microsomal Oxidation www.freelivedoctor.com
    • Preparation Of Microsomes www.freelivedoctor.com
    • Cytochrome P450 fp = NADPH cytochrome P450 reductase, or NADH cytochrome b5 reductase www.freelivedoctor.com
    • Oxidation Of Drugs By Cytochrome P450 www.freelivedoctor.com
    • Oxidation Of Drugs By Cytochrome P450 www.freelivedoctor.com
    • Aliphatic Oxidation www.freelivedoctor.com
    • Aromatic Hydroxylation (1) acetanilid p -hydroxyacetanilid www.freelivedoctor.com
    • Aromatic Hydroxylation (2) www.freelivedoctor.com
    • N-Dealkylation www.freelivedoctor.com
    • O-Dealkylation www.freelivedoctor.com
    • S-Demethylation www.freelivedoctor.com
    • Oxidative Deamination www.freelivedoctor.com
    • S-Oxidation www.freelivedoctor.com
    • N-Oxidation www.freelivedoctor.com
    • N-Hydroxylation www.freelivedoctor.com
    • N-Hydroxylation of AAF N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent www.freelivedoctor.com
    • Oxidative Dehalogenation www.freelivedoctor.com
    • Desulfuration www.freelivedoctor.com
    • Desulfuration www.freelivedoctor.com
    • ISOENZMYES OF CYTOCHROME P450 CYP1A1 CYP1A2 CYP2A6 CYP2B_ CYP2C9 CYP2C19 CYP2D6 CYP2AE1 CYP3A4 CYP3A5 CYP3A7 CYP4A_ www.freelivedoctor.com
    • Cytochrome P450 3A4 (CYP3A4) www.freelivedoctor.com
    • 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
      www.freelivedoctor.com
    • Some Drugs That Inhibit CYP3A4
      • Macrolide antibiotics
        • Erythromycin
        • Clarithromycin
        • Other such agents
      • Antifungal agents
        • Ketoconazole
        • Itraconazole
        • Other such agents
      • HIV protease inhibitors
      www.freelivedoctor.com
    • CYP3A4
      • Ketoconazole and terfenadine can produce a drug interaction with fatal consequences.
      www.freelivedoctor.com
    • CONVERSION OF TERFENADINE TO FEXOFENADINE CYP3A4 O 2, NADPH www.freelivedoctor.com
    • AN INGREDIENT IN GRAPEFRUIT JUICE INHIBITS CYP3A4 www.freelivedoctor.com
    • 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
    • 6',7', - Dihydroxybergamottin www.freelivedoctor.com
    • Grapefruit Juice Consumption Blocks Terfenadine Metabolism to Fexofenadine www.freelivedoctor.com X
    • CYP3A4 And P-Glycoprotein
      • P-Glycoprotein and CYP3A4 control oral bioavailability of many drugs
      • P-Glycoprotein and CYP3A4 share many substrates and inhibitors
      www.freelivedoctor.com
    • 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 www.freelivedoctor.com
    • 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
    • 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
      www.freelivedoctor.com
    • CYP2C 19
      • 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
      www.freelivedoctor.com
    • CYP1A1
      • Polycyclic hydrocarbons are among its substrates
      • Inducers include
        • Polycyclic hydrocarbons such as 3,4,-benzopyrene, 3-methylcholanthrene, etc.
        • Charcoal broiled foods (polycyclic hydrocarbons)
      www.freelivedoctor.com
    • 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
    • NONMICROSOMAL OXIDATIONS ALCOHOL DEHYDROGENATION ALDEHYDE DEHYDROGENATION XANTHINE OXIDATION DIAMINE OXIDATION MONOAMINE OXIDATION www.freelivedoctor.com
    • 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
    • Monoamine Oxidase Metabolism of Serotonin www.freelivedoctor.com
    • Some Popular Substrates of Monoamine Oxidase
      • Serotonin
      • Epinephrine
      • Norepinephrine
      • Dopamine
      • Tyramine (found in certain foods)
      www.freelivedoctor.com
    • Diamine Oxidase cadaverine www.freelivedoctor.com
    • 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
      www.freelivedoctor.com
    • Alcohol Dehydrogenase CH 3 CH 2 OH + NAD +  CH 3 CHO + NADH + H + ethanol acetaldehyde www.freelivedoctor.com
    • Aldehyde Dehydrogenase CH 3 CHO + NAD +  CH 3 COOH + NADH + H + acetaldehyde acetate www.freelivedoctor.com
    • XANTHINE OXIDASE www.freelivedoctor.com
    • Xanthine Oxidase www.freelivedoctor.com
    • REDUCTION www.freelivedoctor.com
    • Nitro Reduction Microsomes and cytosol www.freelivedoctor.com
    • Nitro Reduction www.freelivedoctor.com
    • Azo Reduction Microsomes and cytosol www.freelivedoctor.com
    • Azo Reduction Microsomes and cytosol www.freelivedoctor.com
    • Alcohol Dehydrogenation Cytosol www.freelivedoctor.com
    • DIHYDROPYRIMIDINE DEHYDROGENASE
      • 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 www.freelivedoctor.com 5-Fluorouracil 5-Fluoro-5,6-dihydrouracil DPYD
    • HYDROLYSIS www.freelivedoctor.com
    • Amide Hydrolysis Microsomes and cytosol www.freelivedoctor.com
    • Ester Hydrolysis Microsomes and cytosol www.freelivedoctor.com
    • Ester Hydrolysis Microsomes and cytosol Enalaprit www.freelivedoctor.com
    • EPOXIDE HYDROLASE www.freelivedoctor.com
    • Epoxide Hydrolase
      • A microsomal enzyme
      www.freelivedoctor.com
    • Epoxide Hydrolase www.freelivedoctor.com
    • www.freelivedoctor.com
    • PHASE II METABOLIC PATHWAYS www.freelivedoctor.com
    • 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
    • PHASE II REACTIONS Glucuronidation Sulfate Conjugation Acetylation Glycine Conjugation Methylation Transulfuration Glutathione Conjugation Mercapturic Acid Synthesis www.freelivedoctor.com
    • GLUCURONIDATION www.freelivedoctor.com
    • 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
    • UDP-  -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
      www.freelivedoctor.com
    • Glucuronidation of Benzoic Acid UGT= UDP-  -D-Glucuronsyltransferase www.freelivedoctor.com
    • Glucuronidation of Aniline www.freelivedoctor.com
    • Glucuronidation of p -Hydroxyacetanilid www.freelivedoctor.com
    • 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
    • Morphine Metabolism Morphine -3-glucuronide is the major metabolite www.freelivedoctor.com
    • Induction Of UDP-  -D-Glucuronyl Transferase
      • Induced by phenobarbital
      • Induced by 3-methylcholanthrene
      www.freelivedoctor.com
    • Glucuronidation in the Cat
      • The cat can glucuronidate bilirubin but cannot glucuronidate phenolic compounds such as phenol and napthol
      www.freelivedoctor.com
    • SULFATE CONJUGATION www.freelivedoctor.com
    • 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
      www.freelivedoctor.com
    • 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
    • Sulfate Conjugation of p -Hydroxyacetanilid PAP: 3’-phosphoadenosine- 5’-phosphate www.freelivedoctor.com
    • MINOXIDIL METABOLISM MINOXIDIL N-O-GLUCURONIDE (inactive metabolite) www.freelivedoctor.com MINOXIDIL (inactive) MINOXIDIL N-O-SULFATE (active metabolite)
    • Species Differences in Sulfate Conjugation
      • Some species are deficient in the sulfate conjugation pathway
        • Pig
        • Opposum
      www.freelivedoctor.com
    • N-ACETYLATION www.freelivedoctor.com
    • 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
      www.freelivedoctor.com
    • 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
    • N-Acetyltransferase www.freelivedoctor.com
    • N-Acetyltransferase
      • The dog cannot acetylate aromatic amino compounds because it lacks the appropriate isoenzyme of NAT
      www.freelivedoctor.com
    • SUGAR CONJUGATION www.freelivedoctor.com
    • Conversion of 6-Mercaptopurine to a Nucleotide www.freelivedoctor.com
    • METHYLATION www.freelivedoctor.com
    • 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
    • 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
      www.freelivedoctor.com
    • N-Methyltransferases PNMT- Phenylethanolamine-N-methyltransferase www.freelivedoctor.com Norepinephrine Epinephrine PNMT SAM
    • O-Methylation Of Catecholamines COMT- catechol-O-methyltransferase www.freelivedoctor.com
    • O-Methylation of Norepinephrine COMT- catechol-O-methyltransferase www.freelivedoctor.com
    • 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
    • METABOLISM OF MERCAPTOPURINE (1)
      • TMPT -Thiomethylpurinetransferase
        • Conducts S-methylation of the substrate
        • Found in RBC’s
        • Isoforms exist
          • active enzyme
          • inactive enzyme
      www.freelivedoctor.com 6-Mercaptopurine 6-Methylmercaptopurine TMPT
    • AMINO ACID CONJUGATION www.freelivedoctor.com
    • AMINO ACID CONJUGATION (mitochondria) www.freelivedoctor.com
    • Multiple Metabolic Pathways Exist for Aspirin’s Metabolism Hydolysis of aspirin produces salicyclic acid, as seen in the next slide www.freelivedoctor.com
    • 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
    • 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
      www.freelivedoctor.com
    • TRANSULFURATION www.freelivedoctor.com
    • TRANSULFURATION www.freelivedoctor.com
    • GLUTATHIONE CONJUGATION www.freelivedoctor.com
    • DRUG INTERACTION WITH GLUTATHIONE mercapturate metabolite of drug www.freelivedoctor.com
    • 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”
      www.freelivedoctor.com
    • ACETAMINOPHEN METABOLISM www.freelivedoctor.com
    • Bioactivation of Acetaminophen www.freelivedoctor.com
    • 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
    • ACETAMINOPHEN AND ITS PHASE I METABOLITES www.freelivedoctor.com
    • 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
    • N-ACETYLCYSTEINE FOR ACETAMINOPHEN TOXICITY www.freelivedoctor.com
    • CARCENOGENSIS www.freelivedoctor.com
    • N-Hydroxylation of AAF N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent www.freelivedoctor.com
    • 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
    • CYP1A1 Converts Benzopyrene to a Carcinogen www.freelivedoctor.com
    • Aflatoxin is Metabolized to a Carcinogenic Agent www.freelivedoctor.com
    • FACTORS AFFECTING DRUG METABOLISM www.freelivedoctor.com
    • ENZYME INDUCTION www.freelivedoctor.com
    • www.freelivedoctor.com
    • www.freelivedoctor.com
    • 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
      www.freelivedoctor.com
    • AGE www.freelivedoctor.com
    • FACTORS AFFECTING DRUG METABOLISM
      • Age
        • Neonates
        • Children
        • Elderly
      www.freelivedoctor.com
    • DIET www.freelivedoctor.com
    • 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)
      www.freelivedoctor.com
    • GENETIC VARIATION www.freelivedoctor.com
    • 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
      www.freelivedoctor.com
    • STATE OF HEALTH www.freelivedoctor.com
    • FACTORS AFFECTING DRUG METABOLISM
      • State of health
        • Hepatitis
        • Liver cancer
        • Cardiac insufficiency
        • Uremia
          • degree of protein binding
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    • Changes In Drug Metabolism As A Consequence Of Hepatic Disease From Principles of Drug Action www.freelivedoctor.com
    • GENDER www.freelivedoctor.com
    • FACTORS AFFECTING DRUG METABOLISM
      • Gender
        • Most studies are performed in the rat. In general, male rats metabolize drugs faster than female rats
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    • DEGREE OF PROTEIN BINDING www.freelivedoctor.com
    • 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
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    • SPECIES VARIATION www.freelivedoctor.com
    • FACTORS AFFECTING DRUG METABOLISM
      • Species variation
        • Quantitative
        • Qualitative
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    • 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
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    • SUBSTRATE COMPETITION www.freelivedoctor.com
    • 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
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