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Pharmacogenomics: Understanding the Host and Drug Interface

Pharmacogenomics: Understanding the Host and Drug Interface. Stephen Becker. The Treatment Triad: Defining the Interfaces. Patient. Virus. Drug. The Treatment Triad: Defining the Interfaces. Patient. Virus. Drug. U.S. Drug Approval and Safety 1975-1999. Lasser, JAMA, 2002.

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Pharmacogenomics: Understanding the Host and Drug Interface

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  1. MAR 891_Becker_03 Pharmacogenomics: Understanding the Host and Drug Interface Stephen Becker

  2. MAR 891_Becker_03

  3. MAR 891_Becker_03 The Treatment Triad: Defining the Interfaces Patient Virus Drug

  4. MAR 891_Becker_03 The Treatment Triad: Defining the Interfaces Patient Virus Drug

  5. MAR 891_Becker_03 U.S. Drug Approval and Safety 1975-1999 Lasser, JAMA, 2002

  6. MAR 891_Becker_03 U.S. Drug Approval and Safety 1975-1999 Lasser, JAMA, 2002

  7. MAR 891_Becker_03 U.S. Drug Approval and Safety 1975-1999 Lasser, JAMA, 2002

  8. MAR 891_Becker_03 Drug Approval and Safety 1975-1999 • Drug categories with black box warning • Cardiovascular: 17 • Antiviral agents: 6 • Antineoplastics: 5 • Drug categories of withdrawn agents • Analgesics/NSAIDs: 4 • Cardiovascular: 4 • Antihistamines: 2 Lasser, JAMA, 2002

  9. MAR 891_Becker_03 Pharmacokinetics, Pharmacodynamics and Pharmacogenomics SXR 100% 3A4 P-gp

  10. MAR 891_Becker_03 Pharmacokinetics, Pharmacodynamics and Pharmacogenomics SXR P450system 75% 100% 3A4 P-gp

  11. MAR 891_Becker_03 Pharmacokinetics, Pharmacodynamics and Pharmacogenomics SXR P450system 50% P-gp 75% 100% 3A4 P-gp

  12. MAR 891_Becker_03 Drug Metabolism Mechanisms • Phase I Reactions: Cytochrome P450 • Phase II Reactions: Conjugative enzyme systems

  13. MAR 891_Becker_03 Drug Metabolism Mechanisms • Phase I Reactions: Cytochrome P450 • 3A4, 2D6 and 2C19 account for metabolism of>75% all drugs • Phase II Reactions: Conjugative enzyme systems

  14. MAR 891_Becker_03 Drug Metabolism Mechanisms • Phase I Reactions: Cytochrome P450 • 3A4, 2D6 and 2C19 account for metabolism of>75% all drugs • Significant variability of 2D6 and 2C family • Phase II Reactions: Conjugative enzyme systems

  15. MAR 891_Becker_03 Drug Metabolism Mechanisms • Phase I Reactions: Cytochrome P450 • 3A4, 2D6 and 2C19 account for metabolism of>75% all drugs • Significant variability of 2D6 and 2C family • Levels of 3A4 may vary 60-fold in population • Phase II Reactions: Conjugative enzyme systems

  16. MAR 891_Becker_03 Drug Metabolism Mechanisms • Phase I Reactions: Cytochrome P450 • 3A4, 2D6 and 2C19 account for metabolism of>75% all drugs • Known variability of 2D6 and 2C family • Levels of 3A4 may vary 60-fold in population • Phase II Reactions: Conjugative enzyme systems • N-acetyltransferase (NAT) and INH neurotoxicity

  17. MAR 891_Becker_03 Drug Metabolism Mechanisms • Phase I Reactions: Cytochrome P450 • 3A4, 2D6 and 2C19 account for metabolism of>75% all drugs • Known variability of 2D6 and 2C family • Levels of 3A4 may vary 60-fold in population • Phase II Reactions: Conjugative enzyme systems • N-acetyltransferase (NAT) and INH neurotoxicity • Alcohol dehydrogenase, deficient in whites (5%), blacks (15%), Japanese (65%)

  18. MAR 891_Becker_03 Pharmacokinetics, Pharmacodynamics and Pharmacogenomics SXR P450system 50% P-gp 75% 100% 3A4 P-gp

  19. MAR 891_Becker_03 Age Gender Race Body mass index Alcohol Tobacco Diet Co-morbid conditions Concomitant conditions Altered organ function Genetics Factors Altering CYP450 Function

  20. MAR 891_Becker_03 Age Gender Race Body mass index Alcohol Tobacco Diet Co-morbid conditions Concomitant conditions Altered organ function Genetics Factors Altering CYP450 Function

  21. MAR 891_Becker_03 Age Gender Race Body mass index Alcohol Tobacco Diet Co-morbid conditions Concomitant conditions Altered organ function Genetics Factors Altering CYP450 Function

  22. MAR 891_Becker_03 Age Gender Race Body mass index Alcohol Tobacco Diet Co-morbid conditions Concomitant conditions Altered organ function Genetics Factors Altering CYP450 Function

  23. MAR 891_Becker_03 Age Gender Race Body mass index Alcohol Tobacco Diet Co-morbid conditions Concomitant conditions Altered organ function Genetics Factors Altering CYP450 Function

  24. MAR 891_Becker_03 CYP 450 System • CYP families 1-3 • Catalyze xenobiotic compounds • CYP families > 4 • Biosynthesis and degradation of hormones, signaling molecules and retinoic acid derivatives

  25. MAR 891_Becker_03 Alleles Cytochrome P450 Nomenclature 2C9*1*2 Family Sub-family Enzyme/gene

  26. MAR 891_Becker_03 Drug Metabolism by the CYP 450 Enzyme Systems 2C9 3A4 2C19 2D6

  27. MAR 891_Becker_03 CYP Isoenzyme Systems Substrate

  28. MAR 891_Becker_03 CYP Isoenzyme Systems Induction Substrate

  29. MAR 891_Becker_03 CYP Isoenzyme Systems Induction Substrate X Inhibition

  30. MAR 891_Becker_03 3A4 Isoenzyme Substrates Benzos, statins Oral contraceptives Macrolides HIV protease inhibitors

  31. MAR 891_Becker_03 3A4 Isoenzyme Induction Steroids Phenobarb Herbals Rifamycins Phenytoin

  32. MAR 891_Becker_03 3A4 Isoenzyme Induction Inhibitors Macrolides Azoles Ca+ blockers Ritonavir CSA X

  33. MAR 891_Becker_03 Herbal and Nutraceutical Interactions with CYP450 3A4 Isoenzyme • Echinacea • Garlic pills • Grapefruit juice • Seville orange juice • Milk thistle • St. John’s wort

  34. MAR 891_Becker_03 Herbal and Nutraceutical Interactions with CYP450 3A4 Isoenzyme • Echinacea • Garlic pills • Grapefruit juice • Seville orange juice • Milk thistle • St. John’s wort Will alter the metabolism of substrates of 3A4 system. Interactions have clinical significance

  35. MAR 891_Becker_03 Poor Metabolizer Ultra-Metabolizer Multiple genes Deleted gene Diminished Response Normal Response Toxicity Genetic Determinants of Metabolism and Predicted Clinical Outcome

  36. MAR 891_Becker_03 Variability in Enzymatic Expression 1000-fold 20-fold Poor Metabolizer Extensive Metabolizer Normal Metabolizers

  37. MAR 891_Becker_03 Enzyme Expression and HIV Status HIV - HIV + 3A4 2D6 1A2 Kashuba,2001

  38. MAR 891_Becker_03 Enzyme Expression and HIV Disease State HIV, aviremic HIV, viremic 3A4 AAG P-gp

  39. MAR 891_Becker_03 Gender and Pharmacology: How Little We Know • Pharmacology substudy of ACTG 359, n = 186 • Measured SQV exposures. In females: • Clearance was 46% of that for males • AUC was therefore increased by 50% • Half-life prolonged by 50-100% Brundage, CROI, 2002

  40. MAR 891_Becker_03 Drug Metabolizing Enzymes and Allelic Mutants Norweg,Ash Jews Armenian Chinese New Guinean Bantu, Ethiop, Afro-Caribb

  41. MAR 891_Becker_03 Nelfinavir Pharmacokinetics • Lag time in absorption, 1-2 hours • Circadian rhythm with AM troughs2 to 3-fold higher than PM levels • Active metabolite, M8 • M8 felt to contribute to antiviral effect equal to parent compound

  42. MAR 891_Becker_03 NFV and M8 Metabolism 3A4 NFV 2C19 M8 NFV 2D6 NFV

  43. MAR 891_Becker_03 NFV and M8 Metabolism 3A4 M8 NFV 2C19 NFV M8 2D6 NFV

  44. MAR 891_Becker_03 NFV and M8 PK in the Settingof 2C19 Polymorphism 3A4 NFV 2C19 NFV M8 2D6 NFV

  45. MAR 891_Becker_03 M8 and Nelfinavir Levels by Race(Ratio Compared to PK Population) White Black Asian NFV 1.07 1.17 1.23 M8 1.02 0.62 0.52 M8/NFV Ratio 0.30 0.20 0.19 Baede-van Dijk, 2001

  46. MAR 891_Becker_03 Effect of 2C19 Polymorphisms on Omeprazole Exposure Brockmoller, Clin. Pharmacol. Ther., 1997

  47. MAR 891_Becker_03 Drug Metabolizing Enzymes and Allelic Mutants Norweg,Ash Jews Armenian Chinese New Guinean Bantu, Ethiop, Afro-Caribb

  48. MAR 891_Becker_03 Dose Alteration Based on CYP Genotype Brockmoller, Pharmacogenomics, 2000

  49. MAR 891_Becker_03 Dose Alteration Based on CYP Genotype Brockmoller, Pharmacogenomics, 2000

  50. MAR 891_Becker_03 Pharmacokinetics, Pharmacodynamics and Pharmacogenomics SXR P450system 50% P-gp 75% 100% 3A4 P-gp

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