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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DIG-F (02))
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Okita, Richard T
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University of Minnesota Twin Cities
Schools of Pharmacy
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Flora, Darcy R; Tracy, Timothy S (2012) Development of an in vitro system with human liver microsomes for phenotyping of CYP2C9 genetic polymorphisms with a mechanism-based inactivator. Drug Metab Dispos 40:836-42
Subramanian, Murali; Agrawal, Vishal; Sandee, Duanpen et al. (2012) Effect of P450 oxidoreductase variants on the metabolism of model substrates mediated by CYP2C9.1, CYP2C9.2, and CYP2C9.3. Pharmacogenet Genomics 22:590-7
Sandee, Duanpen; Morrissey, Kari; Agrawal, Vishal et al. (2010) Effects of genetic variants of human P450 oxidoreductase on catalysis by CYP2D6 in vitro. Pharmacogenet Genomics 20:677-86
Hutzler, J Matthew; Balogh, Larissa M; Zientek, Michael et al. (2009) Mechanism-based inactivation of cytochrome P450 2C9 by tienilic acid and (+/-)-suprofen: a comparison of kinetics and probe substrate selection. Drug Metab Dispos 37:59-65
Hummel, Matthew A; Gannett, Peter M; Aguilar, Jarrett et al. (2008) Substrate proton to heme distances in CYP2C9 allelic variants and alterations by the heterotropic activator, dapsone. Arch Biochem Biophys 475:175-83
Kramer, Melissa A; Tracy, Timothy S (2008) Studying cytochrome P450 kinetics in drug metabolism. Expert Opin Drug Metab Toxicol 4:591-603
Kumar, Vikas; Brundage, Richard C; Oetting, William S et al. (2008) Differential genotype dependent inhibition of CYP2C9 in humans. Drug Metab Dispos 36:1242-8
Wei, Lian; Locuson, Charles W; Tracy, Timothy S (2007) Polymorphic variants of CYP2C9: mechanisms involved in reduced catalytic activity. Mol Pharmacol 72:1280-8
Kumar, Vikas; Wahlstrom, Jan L; Rock, Dan A et al. (2006) CYP2C9 inhibition: impact of probe selection and pharmacogenetics on in vitro inhibition profiles. Drug Metab Dispos 34:1966-75
Kumar, Vikas; Locuson, Chuck W; Sham, Yuk Y et al. (2006) Amiodarone analog-dependent effects on CYP2C9-mediated metabolism and kinetic profiles. Drug Metab Dispos 34:1688-96

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