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PHAR 751 Pharmacogenomics

PHAR 751 Pharmacogenomics. Sarah Brown, Pharm.D. Pharmacy Practice Resident Asante Health System sbrown@asante.org. PK: p-gp & sex, racial background. ∆ Males ■ Females ○ African Americans ▼European Americans.  No difference between groups. Genotype vs. Phenotype: exon 26.

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PHAR 751 Pharmacogenomics

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  1. PHAR 751 Pharmacogenomics Sarah Brown, Pharm.D. Pharmacy Practice Resident Asante Health System sbrown@asante.org

  2. PK: p-gp & sex, racial background ∆ Males ■ Females ○ African Americans ▼European Americans  No difference between groups

  3. Genotype vs. Phenotype: exon 26 MDR1 exon 26, C3435T □ CT ■ CC ○ TT P=0.036 CC vs. TT 180 mg fexofenadine po

  4. Genotype vs. Phenotype: exon 21 MDR1 exon 21, G2677T □ GT ■ GG ○ TT P= 0.054 GG vs. TT

  5. Genotype vs. Phenotype MDR1*1 or MDR1*2 alleles □ *1*2 ■ *1*1 ○ *2*2

  6. Study conclusions • Multiple SNPs present in the human MDR1 gene • Polymorphism alters p-gp activity • Genetic variation differs d/t racial background

  7. Another Fexofenadine, p-gp study • Is the disposition of fexofenadine in humans affected by polymorphisms of MDR1? • TT genotype vs. CC genotype Drescher, et al. MDR1 gene polymorphisms and disposition of the p-glycoprotein substrate fexofenadine. Br J Clin Pharmacol 2002;53:526-534.

  8. CC vs. TT genotype ■ CC ○ TT Fexofenadine concentration vs. Time Drescher, et al. MDR1 gene polymorphisms and disposition of the p-glycoprotein substrate fexofenadine. Br J Clin Pharmacol 2002;53:526-534.

  9. GG vs. TT phenotype ■ GG ○ TT  Not significant Fexofenadine concentration vs. Time Drescher, et al. MDR1 gene polymorphisms and disposition of the p-glycoprotein substrate fexofenadine. Br J Clin Pharmacol 2002;53:526-534.

  10. Different conclusions? • This study: NS difference in PK of fexofenadine • Known: fexofenadine is a p-gp substrate • Unknown: lack of association btwn PK and polymorphism

  11. Polymorphisms: Enzymes • Frequently polymorphic • Phenotypic consequence • Leads to inter-individual variability in drug response? • Other factors: molecular basis, expression of other drug-metabolizing enzymes, concurrent medications or illnesses

  12. Consequences of enzyme polymorphisms: Drug toxicities • Thiopurine methyltransferase-deficiency • Hematopoietic toxicity when treated w/ standard doses of azathioprine or mercaptopurine • Slow acetylator phenotype • Hydralazine-induced lupus • Isoniazid-induced neuropathies • Dye-associated bladder cancer • Sulfonamide-induced hypersensitivity rxns

  13. NAT2 polymorphism: Isoniazid Slow acetylator vs. Fast acetylator

  14. N-acetyltransferase (NAT2) polymorphism • Europe, North America: 40 – 70% slow acetylators (SA) • Pacific Asian: 10 – 30% SA • Egyptian and Moroccan: 80 – 90% SA • Canadian Eskimo: 5% SA

  15. Acebutolol (a) Isoniazid Aminobenzoic Acid Nitrazepama Aminogluthethimide Phenelzine Aminosalicylic Acid Procainamide Amrinone Sulfadiazine Caffeine (a) Sulfamerazine Clonazepam Sulfamethazine Dapsone Sulfapyridine Hydralazine Sulfasalazine Agents Undergoing Polymorphic N-acetylation (a) =Requires metabolism before N-acetylation

  16. CYP2C polymorphisms

  17. Consequences of enzyme polymorphisms • ↑ CYP1A activity + slow acetylation = ↓ myelosuppression from active metabolites of amonafide • ↓ drug-metabolizing enzyme  ↓ pro-drug activation • CYP2D6, opioid analgesics

  18. PK: Ethnic differences • Unlikely: • No gut or hepatic first-pass effect • Low plasma protein-binding (<70-80%) • No/minimal hepatic metabolism • No/minimal renal tubular secretion • Likely: • Gut or hepatic metabolism • High plasma protein-binding • Hepatic metabolism as major route

  19. Chinese vs. Caucasians Higher metabolism Propranolol Morphine No difference Triazolam Cerivastatin Lower metabolism Desipramine Alprazolam Diazepam Omeprazole Nifedipine Codeine Ethnic differences: hepatic metabolism

  20. African descent vs. Caucasians Higher metabolism Propranolol Lower metabolism Nifedipine Methyprednisolone Phenytoin No difference Metoprolol/labetolol Albuterol Terbutaline Trimazosin Procainamide Etoposide Ethnic differences: hepatic metabolism

  21. Ethnic variations • Passive absorption, filtration at the glomerulus, and passive tubular reabsorption will not differ between ethnic groups • For many drugs, PK prediction is difficult

  22. Genetic testing • Carrier testing • Diagnostic testing • Newborn screening • Pharmacogenetic testing

  23. Clinical Relevance • Small numbers of patients • Availability of genotyping and phenotyping tools • Genetic testing • Predicting • Drug interactions • Therapeutic window • In practice…

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