Data are accumulating to suggest that genetic variation in human drug metabolizing enzymes can profoundly affect not only the rate of drug metabolism but also the degree of drug-drug interactions observed upon concomitant drug dosing. The long term goals of this research are to understand the effects of genetic polymorphisms in P450 enzymes on susceptibility to drug- drug interactions and to develop models to predict these changes in interaction potential;quantifying these effects will improve the accuracy of clinical dosing adjustments. A major finding from the previous granting period was that CYP2C9 variants with reduced function (i.e., CYP2C9*3) exhibit altered degrees of inhibition in both an in vitro model and in an initial in vivo human clinical study of the interaction of flurbiprofen (CYP2C9 probe substrate) and fluconazole (CYP2C9 inhibitor). Implicit in this finding is the hypothesis that an interplay between fraction of drug metabolized by CYP2C9 and genotype determines the extent of drug interaction observed. This preliminary study has significant clinical importance as it suggests that individuals of differing genotypes may require different adjustments of doses upon drug co-administration and in particularly for narrow therapeutic index drugs, such as phenytoin. The current competing renewal builds upon the above findings to: a) validate an enzyme-based pharmacokinetic model that uses a genotype-specific inhibition constant (Ki) to determine the extent of the drug interaction and the impact on the fraction of drug metabolized, and b) develop an in vitro model of homozygous poor metabolism and heterozygous partial null metabolism for predicting genotype-dependent drug-drug interactions. Through enhanced understanding of the effect of genotype on interactions and development of a predictive model that utilizes both in vitro data and known metabolism characteristics of the compound of interest, drug interactions can be managed more effectively resulting in improved patient outcomes.
A person's genetic makeup can affect drug disposition and action, as well as the susceptibility to drug interactions. Improved understanding of these genetic changes and their effects on drug disposition will lead to improved drug therapy and better management of drug-drug interactions.
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