Polymorphisms in cytochrome P450 enzymes, such as CYP2C9 and CYP2D6, may not only affect drug clearance but may affect patient's susceptibility to drug inhibition interactions. The long term goal of this research is to understand the role of amino acid substitution due to polymorphisms in P450 enzymes in the relative susceptibility to drug-drug interactions. The metabolism of several clinically relevant drugs is greatly diminished in subjects with CYP2C9 and CYP2D6 polymorphisms, necessitating dosage adjustments. Since amino acid changes resulting from polymorphisms can affect substrate binding and turnover, inhibitor binding and effect can also be altered. Because substrates and inhibitors may bind within a P450 active site in different orientations, the degree and direction of change in inhibition is likely to be both inhibitor and genotype dependent. The proposed experiments will study common variants of CYP2C9 and CYP2D6 with known inhibitors of these enzymes and assess the degree and type of inhibition observed. T1 NMR experiments will be conducted to determine the distances and relative orientation of substrate and inhibitor from heme iron for incorporation with kinetic data into computer models predictive of drug inhibition potential based on the polymorphic form of the enzyme. Finally, differences in inhibition due to genotype will be tested in vivo with a human clinical study of drug inhibition in patients of two different CYP2C9 genotypes. Taken together, these studies will permit a better understanding of drug inhibition potential in different P450 genotypes and serve as a foundation for increasing our understanding of interindividual differences in susceptibility to drug interactions ? ?
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