DRUG METABOLISM • Metabolism (biotransformation) of compounds is essential for survival of the organism. • Accomplished by a limited number of enzymes with.
Download ReportTranscript DRUG METABOLISM • Metabolism (biotransformation) of compounds is essential for survival of the organism. • Accomplished by a limited number of enzymes with.
DRUG METABOLISM • Metabolism (biotransformation) of compounds is essential for survival of the organism. • Accomplished by a limited number of enzymes with broad and overlapping substrate specificity. • Many of the enzymes are constitutively expressed, but some require the presence of a drug or toxic compound to be induced = enzyme induction. • Primary aims of Metabolism: - the parent molecule is transformed into a more polar metabolite, often by the addition of an ionizable group – usually more H2O-soluble than the parent compound. - MW often increases. - Excretion, and therefore, elimination, facilitated. Consequences of Metabolism • • • • • • The biological t1/2 decreases. Exposure duration decreases. Compound does not accumulate in the body. But biological activity may change. Duration of biological activity may be affected. Although H2O-solubility and elimination are often increases, detoxification is not always the result. Transformation of Xenobiotics by Biological Systems IMPLICATIONS FOR DRUG METABOLISM IMPLICATIONS FOR DRUG METABOLISM 1. Termination of drug action 2. Activation of prodrug 3. Bioactivation and toxication 4. Carcinogenesis 5. Tetratogenesis Termination of Drug Action atropine propranolol (active) tropic acid and tropine hydroxypropranolol (active) Termination of Drug Action Conversion of drug to active metabolite to active metabolite to inactive metabolite Activation of Prodrug L-dopa Dopamine Inactive Terfenadine is Converted to its Active Metabolite Fexofenadine activation of prodrug terfenadine fexofenadine Some Xenobiotics Are Metabolized to Carcinogenic Agents carcinogenesis • 3,4 Benzopyrene • Aflatoxin • N-Acetylaminoflluorene Metabolites of these agents interact with DNA Small Amounts of Acetaminophen is Converted to the Reactive Metabolite N-Acetylbenzoquinoneimine bioactivation Bioactivation of acetaminophen; under certain conditions, the electrophile Nacetylbenzoquinoneimine reacts with tissue macromolecules, causing liver necrosis. 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. FACTORS AFFECTING DRUG METABOLISM 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 Factors Affecting Drug Metabolism • Route of drug administration – Oral versus systemic administration 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 Organ Sites of Drug Metabolism • • • • • • • Liver Small intestine Kidney Skin Lungs Plasma All organs of the body Cellular Sites Of Drug Metabolism • • • • Cytosol Mitochondria Lysosomes Smooth endoplasmic reticulum (microsomes) KINETICS OF DRUG METABOLISM First Order Metabolism A drug may be given in doses that produce blood concentrations less than the Km of the enyzme for the drug. v = Vmax [C] Km + [C] When then Km >>> [C], 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. Zero Order Metabolism A drug may be given in doses that produce blood concentrations greater than the Km of the enyzme for the drug. 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. PHASES OF DRUG METABOLISM Phase I Metabolism Polar groups are exposed on or introduced to a molecule R ROH R RCOOH R RSH R RNH2 Phase I Reactions OXIDATION REDUCTION HYDROLYSIS Phase II Metabolism A molecule endogenous to the body donates a portion of itself to the foreign molecule D+ENDOX DX+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. PHASE I METABOLIC PATHWAYS Microsomal Oxidation Preparation Of Microsomes Cytochrome P450 fp = NADPH cytochrome P450 reductase, or NADH cytochrome b5 reductase Oxidation Of Drugs By Cytochrome P450 Oxidation Of Drugs By Cytochrome P450 Aliphatic Oxidation Aromatic Hydroxylation acetanilid p-hydroxyacetanilid N-Dealkylation O-Dealkylation S-Demethylation Oxidative Deamination S-Oxidation N-Oxidation N-Hydroxylation N-Hydroxylation of AAF N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent Oxidative Dehalogenation Desulfuration Desulfuration ISOENZMYES OF CYTOCHROME P450 CYP1A1 CYP2D6 CYP1A2 CYP2AE1 CYP2A6 CYP3A4 CYP2B_ CYP3A5 CYP2C9 CYP3A7 CYP2C19 CYP4A_ Cytochrome P450 3A4 (CYP3A4) 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 Some Drugs That Inhibit CYP3A4 • Macrolide antibiotics – Erythromycin – Clarithromycin – Other such agents • Antifungal agents – Ketoconazole – Itraconazole – Other such agents • HIV protease inhibitors CYP3A4 • Ketoconazole and terfenadine can produce a drug interaction with fatal consequences. CONVERSION OF TERFENADINE TO FEXOFENADINE O2, NADPH CYP3A4 AN INGREDIENT IN GRAPEFRUIT JUICE INHIBITS CYP3A4 Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression Hours J.Clin. Invest. 99:10, p.2545-53, 1997 6',7', - Dihydroxybergamottin Grapefruit Juice Consumption Blocks Terfenadine Metabolism to Fexofenadine X CYP3A4 And P-Glycoprotein • P-Glycoprotein and CYP3A4 control oral bioavailability of many drugs • P-Glycoprotein and CYP3A4 share many substrates and inhibitors 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 Codeine is a Substrate of CYP2D6 -CH3 (methyl morphine) Consider the variation in codeine’s metabolism among PM, IM, EM, UM individuals 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 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 CYP1A1 • Polycyclic hydrocarbons are among its substrates • Inducers include – Polycyclic hydrocarbons such as 3,4,-benzopyrene, 3-methylcholanthrene, etc. – Charcoal broiled foods (polycyclic hydrocarbons) CIMETIDINE Inhibits CYP450 Metabolism Of Many Drugs Warfarin Triazolam Phenytoin Chlordiazepoxide Metoprolol Carbamazepine Labetalol Quinidine Quinidine Ethanol Caffeine Tricyclic antidepressants Lidocaine Theophylline Metronidazole Alprazolam Calcium channel blockers Diazepam Diazepam Flurazepam Sulfonylureas NONMICROSOMAL OXIDATIONS ALCOHOL DEHYDROGENATION ALDEHYDE DEHYDROGENATION XANTHINE OXIDATION DIAMINE OXIDATION MONOAMINE OXIDATION 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. Monoamine Oxidase Metabolism of Serotonin Some Popular Substrates of Monoamine Oxidase • • • • • Serotonin Epinephrine Norepinephrine Dopamine Tyramine (found in certain foods) Diamine Oxidase cadaverine 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 Alcohol Dehydrogenase CH3CH2OH + NAD+ CH3CHO + NADH + H+ ethanol acetaldehyde Aldehyde Dehydrogenase CH3CHO + NAD+ CH3COOH + NADH + H+ acetaldehyde acetate Xanthine Oxidase Reduction Nitro Reduction • Microsomes and cytosol Azo Reduction Microsomes and cytosol Alcohol Dehydrogenation Cytosol DIHYDROPYRIMIDINE DEHYDROGENASE 5-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 Ester Hydrolysis Enalaprit Microsomes and cytosol Epoxide Hydrolase (microsomes) PHASE II METABOLIC PATHWAYS PHASE II METABOLISM A molecule endogenous to the body donates a portion of itself to the foreign molecule D+ENDOX DX+ENDO PHASE II REACTIONS Glucuronidation Sulfate Conjugation Acetylation Glycine Conjugation Methylation Transulfuration Glutathione Conjugation Mercapturic Acid Synthesis GLUCURONIDATION 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. 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 Glucuronidation of Benzoic Acid UGT= UDP--D-Glucuronsyltransferase Glucuronidation of Aniline Glucuronidation of p-Hydroxyacetanilid Morphine Metabolism Morphine Morphine -6-glucuronide (active metabolite) Morphine Morphine -3-glucuronide (inactive metabolite) A small amount of morphine undergoes N-demethylation Morphine Metabolism Morphine -3-glucuronide is the major metabolite Induction Of UDP--D-Glucuronyl Transferase • Induced by phenobarbital • Induced by 3-methylcholanthrene Glucuronidation in the Cat • The cat can glucuronidate bilirubin but cannot glucuronidate phenolic compounds such as phenol and napthol 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 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. Sulfate Conjugation of p-Hydroxyacetanilid PAP: 3’-phosphoadenosine- 5’-phosphate MINOXIDIL METABOLISM MINOXIDIL MINOXIDIL N-O-SULFATE (inactive) (active metabolite) MINOXIDIL N-O-GLUCURONIDE (inactive metabolite) Species Differences in Sulfate Conjugation • Some species are deficient in the sulfate conjugation pathway – Pig – Opposum N-ACETYLATION 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 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. N-Acetyltransferase N-Acetyltransferase • The dog cannot acetylate aromatic amino compounds because it lacks the appropriate isoenzyme of NAT SUGAR CONJUGATION Conversion of 6-Mercaptopurine to a Nucleotide METHYLATION S-Adenosylmethionine Cytosolic enzymes such as catechol-O-methyl transferase (COMT) and phenylethanolamine-N-methyl transferase (PNMT) conducts the donation of the methyl group from the endogenously synthesized SAM to various substrates to form methylated conjugates. Norepinephrine is N-methylated by PNMT to form epinephrine. Norepinephrine, epinephrine, dopamine, and L-DOPA are O-methylated by COMT. 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 N-Methyltransferases PNMT- Phenylethanolamine-N-methyltransferase Norepinephrine PNMT SAM Epinephrine O-Methylation Of Catecholamines COMT- catechol-O-methyltransferase O-Methylation of Norepinephrine COMT- catechol-O-methyltransferase S-Methylation of 6-Mercaptopurine TPMT - thiopurinemethyltransferase; some individuals are deficient in this enzyme that is critically important for the metabolism of this agent METABOLISM OF MERCAPTOPURINE (1) 6-Mercaptopurine TMPT 6-Methylmercaptopurine • TMPT -Thiomethylpurinetransferase – Conducts S-methylation of the substrate – Found in RBC’s – Isoforms exist • active enzyme • inactive enzyme AMINO ACID CONJUGATION (mitochondria) Multiple Metabolic Pathways Exist for Aspirin’s Metabolism Hydolysis of aspirin produces salicyclic acid, as seen in the next slide 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. 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 TRANSULFURATION GLUTATHIONE CONJUGATION DRUG INTERACTION WITH GLUTATHIONE mercapturate metabolite of drug 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” ACETAMINOPHEN METABOLISM Bioactivation of Acetaminophen 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. ACETAMINOPHEN AND ITS PHASE I METABOLITES 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 paminophenol. N-ACETYLCYSTEINE FOR ACETAMINOPHEN TOXICITY CARCINOGENESIS N-Hydroxylation of AAF N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent 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 CYP1A1 Converts Benzopyrene to a Carcinogen Aflatoxin is Metabolized to a Carcinogenic Agent Factors Affecting Drug Metabolism • • • • • • • • • Enzyme induction Age Diet Genetic variation State of health Gender Degree of protein binding Species Variation Substrate competition 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 FACTORS AFFECTING DRUG METABOLISM • Age – Neonates – Children – Elderly 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) 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 FACTORS AFFECTING DRUG METABOLISM • State of health – Hepatitis – Liver cancer – Cardiac insufficiency – Uremia • degree of protein binding Changes In Drug Metabolism As A Consequence Of Hepatic Disease From Principles of Drug Action FACTORS AFFECTING DRUG METABOLISM • Gender – Most studies are performed in the rat. In general, male rats metabolize drugs faster than female rats. – Alcohol: men vs. women 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 FACTORS AFFECTING DRUG METABOLISM • Species variation – Quantitative – Qualitative 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 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 Drug interaction Drug interaction can be defined as the modifications of the effects of one drug by the prior or concomitant of another drug (poly-pharmacy) 6.5% of adverse drug reactions in USA were attributed to drug interactions (0.2% of these patients may have life-treatening interactions) The potential drug interactions has been observed to be 17% in surgical patients, 22% in patients in medical wards, 23% in out patients clinics. Many websites exist. E.g., www.drug-interactions.com Increasing risk of death 1 in 10 7 1 in 10 6 5 1 in 10 4 1 in 10 1 in 103 2 1 in 10 Lightning Plane crash Murder Auto-cash Fatal, unexpected drug reaction Drug-Drug interaction may alter drug effect by Additive effect : 1 + 1 =2 Synergistic effect : 1 +1 > 2 Potentiation effect : 1 + 0 =2 Antagonism : 1-1 = 0 Mechanism of drug interaction • Pharmacokinetic interactions – – – – Absorption Distribution Biotransformation*** Excretion • Pharmacodynamic interactions – – – – Receptor interaction Receptor sensitivity Neurotransmitter release/Drug transportation Electrolyte balance • Physiological interactions • Pharmaceutical interactions Drug metabolism interaction Enzyme inducers : increase metabolism of concomitant drug therefor increase drug elimination and decrease drug effect Barbiturate, Rifampin, Phenytoin Enzyme inhibitors : decresae metabolism of concomitant drug therefor decrease drug excretion and increase drug effect Cimetidine, Ketoconazole, Erythromycin, Clarithromycin, Chloramphenicol, Quinidine, Sulphaphenazole Pharmacodynamic interactions • Receptor interaction – Competitive – Non-competitive • Sensitivity of receptor – Number of receptor – Affinity of receptor • Alter neurotransmitter release /drug transportation • Alter water/electrolyte balance Physiological interactions Drug A and Drug B bind to different receptors on the same tissue but give opposite or similar effect Aspirin (anti-platelet) +Warfarin/Coumarin (anticoagulant) Increase bleeding Pharmaceutical interactions • Chemical or physiological interactions – Vitamin C + amphotericin B – Pennicilin + Vitamin C Drug-Food interactions • • • • Grapefruit Grapefruit Grapefruit Grapefruit selectively juice and Terfenadine juice and cyclosporin juice and felodipine contains : furanocoumarin compounds that can inhibit CYP3A4 Drug-Herb interactions Ginko biloba St. John’s wort: CYP3A4 inducer Drug features associated with potential interactions Narrow therapeutic index : – Phenytoin – Cyclosporine – Theophylline Sharp response curve: – Phenytoin – Aminoglycoside – Vancomycin Dose dependent (Michaelis-Menten) kinetic –Phenytoin List of drug the most common interacting drug •Antacids •Cimetidine •Digoxin •Warfarin •Theophylline •Ketoconazole Problem in medical practice same complaints same finding same diagnosis same treatment but differential effect ???? •Possible reasons • Physiological factors • Pathological factors • Food •Drug interaction •Genetic Pharmacogenetics Pharmacogenomics Pharmacology + Genetics/Genomics • The study of how individual’s genetic inheritance affects the body’s response to drugs (efficacy & toxicity) • The use of genetic content of humans for drug discovery Drug tablet Sources of drug variability Release Pharmacokinetics Drug in gut Absorption Drug in blood Distribution Drug in tissues Drug metabolites Pharmacodynamics Desired response Drug in urine/bile Drug at receptor No response Unwanted response Genetic variations in drug response and drug toxicity may result from •Variation in drug metabolizing enzymes • Cytochromes P450 • Thiopurine S-methyltransferase •Variation in drug targets • Beta2-adrenergic receptor • ACE • Dopamine receptor •Variation in drug transporters • P-glycoprotien • Variation in disease modifying genes • Apolipoprotein (APOE) DNA polymorphism Changes in the DNA sequence such as – Nucleotide mutation • The most frequent DNA variation found in the human genome is single nucleotide polymorphism (SNP) – Nucleotide deletion – Nucleotide insertion – Gene deletion – Gene duplication Common genetic polymorphism of human drug metabolizing enzymes Enzyme PM incidence CYP2D6 Caucasians 5-10% Asians 1% CYP2C19 CYP2C9 Thiopurine Smethyltransferase Caucasians 2-5% Asians 7-23% Caucasians < 1% Caucasians & Asians 0.3% Drug substrates Dextromethrophan beta-blockers Antiarrythmics Antidepressants Neuroleptics Mephenytoin Mephobarbital Hexobarbital Diazepam Omeprazole Lansoprasole Tolbutamide (S)-Warfarin Phenytoin NSAIDs Azathioprine 6-Mercaptopurine 6-Thioguanine Morphine Codeine O-demethylation CYP2D6 CYP2D6 PM fail to generate active metabolite No analgesic effect Overactive metabolism can cause adverse events “Normal” Activity Morphine Pro-Drug (Codeine) Enzyme Morphine Morphine Pro-Drug (Codeine) Enzyme Morphine Enzyme Morphine Enzyme Morphine “Ultra-rapid” Activity