Prediction of the effects of genetic polymorphism on the pharmacokinetics of CYP2C9 substrates from in vitro data.
OBJECTIVE
The *2 and *3 alleles of CYP2C9, with decreased enzymatic activity, are highly polymorphic and contribute to inter-individual differences in pharmacotherapy of CYP2C9 substrates. Here, we sought for a simplified theoretical method to predict the pharmacokinetic changes with minimal in vivo data.


METHODS
The changes in clearances of CYP2C9 substrates in subjects with these alleles were quantitatively estimated by parameters from literature data: intrinsic metabolic clearance and the enzyme expression level of mutated CYP2C9, contribution of CYP2C9 to the CYP-mediated clearance (f (m2C9)), and the contribution of the dominant metabolic pathways to the total clearance (f (h)). To validate the accuracy of our prediction, the changes were compared to reported in vivo values.


RESULTS
Sufficient data were available for nine substrates: celecoxib, diclofenac, S-flurbiprofen, losartan, S-phenprocoumon, phenytoin, tolbutamide, torsemide, and S-warfarin. These predicted values, either using the intrinsic clearance specific to each substrate, or the averaged values (*2: 0.66, *3: 0.13, (ratio to *1)), correlated well with observed values (r (2) = 0.812, 0.786, respectively).


CONCLUSIONS
This theoretical method well estimated the quantitative changes in pharmacokinetics of CYP2C9 substrates in subjects with mutated alleles of CYP2C9. This can be applied to drug development even from the early clinical phases.
Kusama
Makiko
M
Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Maeda
Kazuya
K
Chiba
Koji
K
Aoyama
Akinori
A
Sugiyama
Yuichi
Y
D000284:Administration, Oral; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010599:Pharmacokinetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D015203:Reproducibility of Results; D013379:Substrate Specificity
C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases