Prediction of the effects of genetic polymorphism on the pharmacokinetics of CYP2C9 substrates from in vitro data.

摘要: The *2 and *3 alleles of CYP2C9, with decreased enzymatic activity, are highly polymorphic contribute to inter-individual differences in pharmacotherapy CYP2C9 substrates. Here, we sought for a simplified theoretical method predict the pharmacokinetic changes minimal vivo data. clearances substrates subjects these were quantitatively estimated by parameters from literature data: intrinsic metabolic clearance enzyme expression level mutated contribution CYP-mediated (f m2C9), dominant pathways total h). To validate accuracy our prediction, compared reported values. Sufficient data available nine substrates: celecoxib, diclofenac, S-flurbiprofen, losartan, S-phenprocoumon, phenytoin, tolbutamide, torsemide, S-warfarin. These predicted values, either using specific each substrate, or averaged values (*2: 0.66, *3: 0.13, (ratio *1)), correlated well observed (r 2 = 0.812, 0.786, respectively). This quantitative pharmacokinetics CYP2C9. can be applied drug development even early clinical phases.