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Pharmacogenetics: Improvement of Existing Drug Treatments

Pharmacogenetics: Improvement of Existing Drug Treatments. Zhou Yan-Qiong. Background ：. Clinical genetics Cytogenetic Somatic Cell Genetics Biochmical genetics Molecular genetics Cancer genetics Population genetics Immunogenetics Pharmacogenetics Genetic toxicology

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Pharmacogenetics: Improvement of Existing Drug Treatments

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  1. Pharmacogenetics: Improvement of Existing Drug Treatments Zhou Yan-Qiong

  2. Background： • Clinical genetics • Cytogenetic • Somatic Cell Genetics • Biochmical genetics • Molecular genetics • Cancer genetics • Population genetics • Immunogenetics • Pharmacogenetics • Genetic toxicology • Developmental genetics • Behavior genetics

  3. PHARMACOGENETICS The study of genetically controlled variations in drug response

  4. 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%

  5. Normal Distribution Frequency Activity

  6. Polymorphic Distribution

  7. GENETIC POLYMORPHISMS Pharmacokinetic Pharmacodynamic • Receptors • Ion channels • Enzymes • Immune molecules • Transporters • Plasma protein binding • Metabolism

  8. II. Genetic polymorphisms in drug metabolizing enzymes From: Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics into rational therapeutics. Science 286:487-491, 1999.

  9. Genetic polymorphisms in drug metabolizing enzymes • 1. Polymorph of debrisoquine • extensive metabolizer——EM • poor metabolizer ——PM*＞12.6 • recessive transmission,autosomal

  10. DRUGS WHOSE METABOLISM CO-SEGREGATES WITH DEBRISOQUINE alprenolol amitriptyline bufuralol clomipramine codeine desipramine encainide ethylmorphine flecainide fluoxetine guanoxan imipramine metoprolol nortriptyline paroxetine phenformin propafenone propranolol

  11. 2. Polymorph of Mephenetoin： • EM • PM：recessive transmission,autosomal • racial diversify

  12. 3. Glucose-6-phosphate dehydrogenase activity Effects >300 million worldwide CYP MPO PGH Synthase R-NH2 R-NOH ERYTHROCYTE O2 NADP+ or GSSG(?) NAD+ HgbFe+2 HMP Shunt G-6-PD Dependent R-NOH MetHgb Reductase NADPH or GSH(?) HgbFe+3 R-NO NADH GSH Reactive Oxygen Splenic Sequestration Semi-mercaptal SOD Catalase GSH Peroxidase sulfinamide Detoxification Hemolytic Anemia R-NH2

  13. Drugs and Chemicals Unequivocally Demonstrated to Precipitate Hemolytic Anemia in Subjects with G6PD Deficiency Acetanilide Nitrofurantoin Primaquine Methylene Blue Sulfacetamide Nalidixic Acid Naphthalene Sulfanilamide Sulfapyridine Sulfamethoxazole

  14. INCIDENCE OF G6PD DEFICIENCY IN DIFFERENT ETHNIC POPULATIONS Ethnic GroupIncidence(%) Ashkenazic Jews 0.4 Sephardic Jews Kurds 53 Iraq 24 Persia 15 Cochin 10 Yemen 5 North Africa <4 Iranians 8 Greeks 0.7-3

  15. INCIDENCE OF G6PD DEFICIENCY IN DIFFERENT ETHNIC POPULATIONS Ethnic GroupIncidence(%) Asiatics Chinese 2 Filipinos 13 Indians-Parsees 16 Javanese 13 Micronesians <1

  16. 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.

  17. ETHNIC DIFFERENCES IN THE DISTRIBUTION OF ACETYLATOR PHENOTYPE Population% Slow% Hetero Fast% Homo Fast South Indians 59 35.6 5.4 Caucasians 58.6 35.9 5.5 Blacks 54.6 38.6 6.8 Eskimos 10.5 43.8 45.7 Japanese 12 45.3 42.7 Chinese 22 49.8 28.2 From: Kalo W. Clin Pharmacokinet 7:373-4000, 1982.

  18. XENOBIOTICS SUBJECT TO POLYMORPHIC ACETYLATION IN MAN Carcinogenic Arylamines benzidine -naphthylamine 4-aminobiphenyl Hydrazines isoniazid hydralazine phenylzine acetylhydrazine hydrazine Arylamines dapsone procainamide sulfamethazine sulfapyridine aminoglutethimide Drugs metabolized to amines sulfasalazine nitrazepam clonazepam caffeine

  19. ADVERSE EFFECTS TO SULFASALAZINE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE Frequency of side effect Slow AcetylatorsFast Acetylators Side Effect cyanosis hemolysis transient reticulocytosis 9 1 5 0 6 0 Data from: Das et al. N Engl J Med 289:491-495, 1973.

  20. 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.

  21. Distribution of acetylator phenotype in control subjects and those experiencing a sulfonamide hypersensitivity reaction. Rieder et al. Clin Pharmacol Ther 49:13-17, 1991.

  22. UDPGT NAT1 SMX-glucuronide N-acetyl-SMX CYP2C9 MPO PGH SYNTHASE NAT1 Hydroxamic acid Detox Nitroso SMX hydroxylamine O-acetylation N,O-AT Covalent binding to cellular macromolecules/ cytotoxicity Acetoxy ester Detoxified metabolite Hypersensitivity/ Adverse Reaction

  23. 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.

  24. Patients with efficacy in clinical trials Patients without efficacy in clinical trials Predictive of efficacy Predictive of no efficacy

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