Abstract
CYP2C9 is mainly responsible for the metabolic clearance of phenytoin and ( S)-warfarin. We have shown previously that mutations in the CYP2C9 gene are associated with diminished metabolism of ( S)-warfarin, and so we have now studied the metabolism of phenytoin to its primary inactive metabolite, ( S)-pHPPH, by these mutant enzymes. Kinetic parameters were determined for ( S)-pHPPH formation using recombinant CYP2C9 variants purified from insect cells. The data demonstrate that the CYP2C9*3 gene product retains only 4–6% of the metabolic efficiency of the wild-type protein, CYP2C9*1, towards phenytoin and ( S)-warfarin. Consequently, we suggest that homozygous expression of CYP2C9*3 may represent a common genetic basis for (apparently) idiosyncratic toxicities that have been reported for these two low therapeutic index drugs.
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