Monday, 23 May 2005 - 9:45 AM

This presentation is part of: Transporters

Application of drug transport studies to drug discovery and development

Masayo Yamazaki, Merck and Co., West Point, PA

Recently, carrier-mediated transport pathways and specific transporters have been recognized as important determinants of drug disposition and potential targets of drug-drug interactions (DDIs). In the past decade, the availability of in vitro P-glycoprotein (P-gp) overexpressing cells and P-gp deficient mice has paved the way for the investigation of P-gp's role in pharmacokinetics and certain DDIs. P-gp appears to play a major role in the brain penetration of many CNS-acting compounds. In acknowledgment of the importance of P-gp, many pharmaceutical companies have incorporated P-gp assays into early drug discovery and development processes. This presentation will describe our experience using in vitro and in vivo P-gp assays and show how the data from these studies are interpreted with focus on two fundamental questions: (1) Can animal data be directly scaled up to humans? (2) Can in vitro data be accurately extrapolated to the in vivo situation? Application of in vitro drug transport studies to address clinically significant DDIs will also be presented. We examined the effects of fibrates (antilipidaemic) on human organic anion transporting polypeptide 1B1 (OATP1B1), multidrug resistance protein 2 (MRP2), and P-gp to determine if fibrates have the potential to cause DDIs by inhibiting these transporters. Our results showed it is unlikely that fibrates cause any significant DDIs by affecting either MRP2- or P-gp-mediated transport. Some fibrates showed concentration-dependent inhibition of OATP1B1; however, considering the plasma protein binding and IC50 values on OATP1B1 only gemfibrozil appears to have a potential to cause DDIs by inhibiting OATP1B1 at clinically relevant concentrations.

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