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Rx +  =

. Rx +  =. Rx +  =. . Rx +  =. . ????. Differences in genetic constitution. . Rx +  =. . Rx +  =. Rx +  =. . PHARMACOGENETICS. The study of genetically controlled variations in drug response. I. Key Concepts and Terms.

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Rx +  =

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  1. Rx +  = Rx +  =  Rx +  =  ????

  2. Differences in genetic constitution  Rx +  =  Rx +  = Rx +  = 

  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 From Pratt WB,Taylor P. Fig 7-5b

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

  8. From: Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics into rational therapeutics. Science 286:487-491, 1999.

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

  10. A. Atypical Plasma Cholinesterase succinylmonocholine choline Hydrolysis by pseudocholinesterase • a rapid acting, rapid recovery muscle relaxant - 1951 • usual paralysis lasted 2 to 6 min in patients • occasional pt exhibited paralysis lasting hrs • cause identified as an “atypical” plasma cholinesterase

  11. Atypical plasma cholinesterase has 1/100 the affinity for succinylcholine as normal enzyme • occurs in 1:2500 individuals • tested clinically via the abilityof dibucaine to inhibit esterase hydrolysis of benzoylcholine normal enzyme inhibited > 70% abnormal inhibited < 30% Adapted from: Pharmac Ther 47:35-60, 1990.

  12. Atypical plasma cholinesterase has 1/100 the affinity for succinylcholine as normal enzyme • occurs in 1:2500 individuals • tested clinically via the abilityof dibucaine to inhibit esterase hydrolysis of benzoylcholine • Family studiesindicate variability in plasma cholinesterase activity consistent with 2 allelic, autosomal, codominant genes • other variant forms exist as well

  13. B. Glucose-6-phosphate dehydrogenase activity Effects >100 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

  14. 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

  15. 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

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

  17. C. 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.

  18. NAT2*4 NAT2*5A NAT2*6A NAT2*7A NAT1*4 PA DDS SMZ PABA PAS SMX AF Modified from Grant DM. Pharmacogenetics 3:45-52, 1993

  19. 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.

  20. 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

  21. ADVERSE EFFECTS TO SULFASALAZINE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

  22. 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.

  23. 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.

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

  25. 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

  26. D. CYP2D6 ACTIVITY

  27. 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

  28. Plasma metoprolol concentrations in poor () and extensive () metabolizers of debrisoquine after 200 mg of metoprolol tartrate administered orally. Redrawn from Lennard MS, et al. NEJM 307:1558-1560, 1982.

  29. Dose requirements for nortriptyline in patients with different CYP2D6 Phenotypes. From: Meyer U. Lancet 356:1667, 2000.

  30. 6-glucuronidation codeine-6-glucuronide M-6-G O-demethylation M-3-G morphine CYP2D6 normorphine N-demethylation norcodeine- 6-glucuronide norcodeine

  31. Effect of Quinidine on the Analgesic Response to Codeine in Extensive Metabolizers of CYP2D6 (Phenotyped with Dextromethorphan) Data from: Desmeules J, et al. Eur J Clin Pharmacol 41:23:26, 1991

  32. What is the cause of ‘hypermetabolizers’?

  33. Debrisoquine phenotype in subjects with different CYP2D6 genotypes (CYP2D6L)2 - gene duplication; CYP2D6A - single base deletion CYP2D6B - multiple point mutations Data from: Agundez JG et al. Clin Pharmacol Ther 57:265, 1995.

  34. From: Dalen P, et al. Clin Pharmacol Ther 63:444-452, 1998.

  35. E. CYP2C9 ACTIVITY Prescribed Daily Warfarin Dose and CYP2C9 Genotype Warfarin Dose*Genotype 5.63 (2.56) *1/*1 4.88 (2.57) *1/*2 3.32 (0.94) *1/*3 4.07 (1.48) *2/*2 2.34 (0.35) *2/*3 1.60 (0.81) *3/*3 *Data presented as mean (SD) daily dose in mg From: Higashi MK, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287:1690-1698, 2002.

  36. F. THIOPURINE METHYLTRANSFERASE (TPMT)

  37. Distribution of Thiopurine Methyl-transferase Activity. Reproduced from: Weinshelboum RM, Sladek SL. Am J Hum Genet 32:651-662, 1980.

  38. G. GENETIC POLYMORPHISMS, MATERNAL SMOKING AND LOW BIRTH WEIGHT (LBW) 65% of all infant deaths occur among LBW infants, while LBW infants account for 7.6% of all live births Reduction in birth wgt among smoking women GenotypeWeight Reduction CYP1A1 AA 252 g CYP1A1 Aa/aa520 g GST1 AA/Aa 285 g GST1 aa642 g Data from: Wang X, et al. JAMA 287:195-2002, 2002.

  39. Why are some gliomas resistant to nitrosourea alkylating agents? Evidence suggests this may be the result of an epigenetic phenomenon – one that does not involve a change in DNA sequence. MGMT – methylguanine-DNA methyltransferase Methylation of the promoter region of MGMT may silence the gene From: Esteller M, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. NEJM 243:1350-1354, 2000.

  40. From: Esteller M, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. NEJM 243:1350-1354, 2000.

  41. From: Esteller M, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. NEJM 243:1350-1354, 2000.

  42. 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.

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

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