E-learning

• Inherited variability in PK and PD


  Causes variability in drug response and toxicity
• Inherited variability in PK


  • Phase 1 reactions (drug metabolism)
  • Phase II reactions (drug metabolism)
  • Drug transporters
• Phase 1 reactions


  • CYP2C9 enzyme where 1-3% of Caucasians are known to be poor metabolizers of S-warfarin or S-ibuprofen
  • Clinically relevant genetic polymorphisms: CYP2D6, 2C9, 2C19
• Poor metabolizers


  • Minority of general population
  • Defective genotype for isozyme
  • Unable to metabolise drug substrate
• Extensive metabolizers


  • Have standard gene for isozyme
  • Able to metabolize drug substrate normally
• Ultra-rapid metabolizers


  • Enzyme with higher active
  • Multiple copies of gene for the isozyme
• Phase II reactions


  • Uridine diphosphate glucuronyl transferase where 11% of Caucasians and 1-3% of Asians are known to be poor metabolizers of Irinotecan
• Drug transporters


  • OATP1B1 (Simvastatin, some antibiotics)
• Inherited variability in PD


  • Drug response (Therapeutic response)
  • Toxicity (Adverse effects)
• Drug response


  • VKORC1 causing a variation in sensitivity to anticoagulation, with pronounced resistance very occasionally seen in response to warfarin
• Toxicity


  • HLA-B*1502 causing dangerous or even fatal skin conditions like SJS and TEN in response to Carbamazepine (Exclusive in broad areas of Asia)
• Genetic polymorphism


  A variation in the DNA sequence that occurs in a population with a frequency of >1%
• Genetic polymorphisms


  • HLA-B*1502 for carbamazepine, VKORC1 and CYP2C9 for warfarin, UGT*1A1 for Irinotecan
• Phase I enzymes with genetic polymorphisms


  • CYP2D6
  • CYP2C9
  • CYP2C19
• CYP2C9: 7% in Caucasians, <2% in Asians
• CYP2C19: 3-6% in Caucasians, ~20% in Asians
• CYP2D6: 5-10% in Caucasians, >1% in Asians