Pharmacogenomics and its clinical relevance in medicine

  • Personalized medicine via pharmacogenomics is being pursued due to the fact that current medicines for chronic disease states have poor efficacy & many SE
  • Drug response is affected by:  genetics, diet, gender, weight, age, race/ethnicity, disease state, concomitant drugs
  • Pharmacogenetics:  differences in a single gene affecting drug response
  • Pharmacogenomics:  differences in multiple genes affecting drug response
  • SNPs (single base) account for ~80% of genetic variations between humans
  • Phase 1 metabolism:  CYP450
  • Phase 2 metabolism (excretion):  glutathione, N-acetyltransferase

Examples of drug metabolism and drug target pharmacogenomics.

  • 2D6, 2C9 & 2C19:  sites of significant polymorphism
    • 2D6: Codeine, SSRIs, Tamoxifen
      • Poor 2D6 metabolizers (or pts who are on SSRIs)  are more likely to have an increased recurrence of cancer (tamoxifen doesn’t get activated)
        • SSRIs are strong inhibitors of 2D6 & should be avoided w/ Tamoxifen
    • 2C9:  warfarin
      • VKOR also metabolizes warfarin
    • 2C19:  PPIs (inhibitors), Plavix
  • No significant polymorphism of 3A4
  • Roche AmpliChip P450 Testing system:  examines 2D6 & 2C19
  • Irinotecan is metabolized via UGT1A1*28 glucuronidation
    • Known for significant toxicity (diarrhea, neutropenia)
    • Genotyping of this enzyme is possible
  • The substitution of Arg for Gly   or   Ser for Gly   will result in a reduced response to BB
  • HER-2 positive breast cancer patients should be given Trastuzumab (herceptin)

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