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Pharmacogenetics: Improvement of Existing Drug Treatments Zhou Yan-Qiong 1 Background : • • • • • • • • • • • • Clinical genetics Cytogenetic Somatic Cell Genetics Biochmical genetics Molecular genetics Cancer genetics Population genetics Immunogenetics Pharmacogenetics Genetic toxicology Developmental genetics Behavior genetics 2 PHARMACOGENETICS The study of genetically controlled variations in drug response 3 I. Key Concepts and Terms Monogenic: due to allelic variation at a single gene Polygenic: due to variations at two or more genes Polymorphic: frequently occurring monogenic variants occurring at a frequency >1% 4 Frequency Normal Distribution Activity 5 Polymorphic Distribution 6 GENETIC POLYMORPHISMS Pharmacokinetic •Transporters •Plasma protein binding •Metabolism Pharmacodynamic •Receptors •Ion channels •Enzymes •Immune molecules 7 II. Genetic polymorphisms in drug metabolizing enzymes From: Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics into rational therapeutics. Science 286:487-491, 1999. 8 Genetic polymorphisms in drug metabolizing enzymes • 1. Polymorph of debrisoquine • extensive metabolizer——EM • poor metabolizer ——PM*>12.6 • recessive transmission,autosomal 9 DRUGS WHOSE METABOLISM COSEGREGATES WITH DEBRISOQUINE alprenolol amitriptyline codeine desipramine flecainide fluoxetine metoprolol nortriptyline propafenone bufuralol encainide guanoxan paroxetine propranolol clomipramine ethylmorphine imipramine phenformin 10 2. Polymorph of Mephenetoin: • EM • PM:recessive transmission,autosomal • racial diversify 11 3. Glucose-6-phosphate dehydrogenase activity Effects >300 million worldwide RNH2 CYP MPO PGH Synthase R-NOH ERYTHROCYTE HMP Shunt G-6-PD Dependent NADP+ or GSSG(?) NADPH or GSH(?) O2 R-NOH HgbFe+2 R-NO HgbFe+3 GSH Semi-mercaptal sulfinamide MetHgb Reductase Reactive Oxygen NADH Splenic Sequestration SOD Catalase GSH Peroxidase Detoxification RNH2 NAD+ Hemolytic Anemia 12 Drugs and Chemicals Unequivocally Demonstrated to Precipitate Hemolytic Anemia in Subjects with G6PD Deficiency Acetanilide Nitrofurantoin Methylene Blue Sulfacetamide Naphthalene Sulfanilamide Sulfamethoxazole Primaquine Nalidixic Acid Sulfapyridine 13 INCIDENCE OF G6PD DEFICIENCY IN DIFFERENT ETHNIC POPULATIONS Ethnic Group Incidence(%) Ashkenazic Jews 0.4 Sephardic Jews Kurds 53 Iraq 24 Persia 15 Cochin 10 Yemen 5 North Africa <4 Iranians Greeks 8 0.7-3 14 INCIDENCE OF G6PD DEFICIENCY IN DIFFERENT ETHNIC POPULATIONS Ethnic Group Incidence(%) Asiatics Chinese 2 Filipinos 13 Indians-Parsees 16 Javanese 13 Micronesians <1 15 4. N-ACETYLTRANSFERASE ACTIVITY Distribution of plasma isoniazid concentration in 483 subjects after and oral dose. Reproduced from Evans DAP. Br Med J 2:485, 1960. 16 ETHNIC DIFFERENCES IN THE DISTRIBUTION OF ACETYLATOR PHENOTYPE Population South Indians Caucasians Blacks Eskimos Japanese Chinese % Slow % Hetero Fast 59 58.6 54.6 10.5 12 22 35.6 35.9 38.6 43.8 45.3 49.8 % Homo Fast 5.4 5.5 6.8 45.7 42.7 28.2 From: Kalo W. Clin Pharmacokinet 7:373-4000, 1982. 17 XENOBIOTICS SUBJECT TO POLYMORPHIC ACETYLATION IN MAN Hydrazines Arylamines isoniazid dapsone hydralazine procainamide phenylzine sulfamethazine acetylhydrazine sulfapyridine hydrazine aminoglutethimide Carcinogenic Arylamines benzidine -naphthylamine 4-aminobiphenyl Drugs metabolized to amines sulfasalazine nitrazepam clonazepam caffeine 18 ADVERSE EFFECTS TO SULFASALAZINE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE Frequency of side effect Slow Acetylators Fast Acetylators Side Effect 9 1 cyanosis 5 0 hemolysis 6 0 transient reticulocytosis Data from: Das et al. N Engl J Med 289:491-495, 1973. 19 Relationship Between Onset of Lupus Syndrome in Fast and Slow Acetylators Receiving Procainamide. Data from: Woosley RL, et al. N Engl J Med 298:1157-1159, 1978. % of pts with lupus 120 100 80 60 Slow Acetylators 40 Fast Acetylators 20 0 0 20 40 60 80 100 Duration of Therapy (months) 20 Distribution of acetylator phenotype in control subjects and those experiencing a sulfonamide hypersensitivity reaction. Rieder et al. Clin Pharmacol Ther 49:13-17, 1991. Percentage of Subjects 100 Control HS 80 60 40 20 0 SLOW FAST 21 O SMX-glucuronide UDPGT NH 2 S O H N NAT1 CH 3 N O N-acetyl-SMX Sulfamethoxazole (SMX) CYP2C9 MPO PGH SYNTHASE Detox Nitroso SMX hydroxylamine NAT1 O-acetylation Hydroxamic acid N,O-AT Covalent binding to cellular macromolecules/ cytotoxicity Acetoxy ester Detoxified metabolite Hypersensitivity/ Adverse Reaction 22 Future Role of SNPs and Pharmacogenetics SNP - Single Nucleotide Polymorphisms ……. G G T A A C T G …… ……. G G C A A C T G …... AS of February 2001, 1.42 million SNPs had been identified in the human genome. 23 Patients with efficacy in clinical trials Patients without efficacy in clinical trials Predictive of efficacy Predictive of no efficacy 24