This interdisciplinary program project grant involves four highly collaborative projects and three Core elements involving faculty from five departments of the Schools of Pharmacy and Medicine of the University of Washington and collaboration with two other institutions. Collectively, it is focused (i) on understanding molecular mechanisms that complicate prediction of drug-drug interactions from in vitro data, and (ii) developing methods to allow the prediction of such events from in vitro experiments before humans are exposed to dangerous combinations of drugs in vivo. Project 1 will define the influence of genotype on the magnitude of inhibitory and inductive drug-drug interactions involving the oral anticoagulant drug, warfarin. This information can guide management of warfarin drug interactions in carriers of common polymorphisms within genes controlling the pharmacokinetics and pharmacodynamics of the drug. Interactions involving alkylamine drugs are often complicated by time-dependent inhibition of P450s through formation of a metabolite-intermediate (Ml) complex. Project 2 is pioneering the concept that formation of secondary hydroxylamine metabolites of alkylamine drugs are the pivotal step in Ml complex formation in vitro and in vivo. Extrapolating from in vitro kinetic data to the in vivo situation is further complicated by the phenomenon of P450 allosterism. Project 3 is studying the mechanistic underpinning for activation kinetics among human P450s and will also test if such allosteric behavior occurs in vivo. Finally, Project 4 addresses the quantitative prediction of P-glycoprotein based drug-drug interactions at the human blood-brain barrier. These studies are possible because of novel and innovative imaging methodologies developed by this project that will be used combination with cell model systems and rodent studies.
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