Application of Drug Transport Studies to Preclinical Drug Discovery and Development: Functional Analysis of Transporters, Species Differences, and In Vitro In Vivo Correlation

Historically, the properties defining pharmacokinetic parameters were largely attributed to passive processes defined by the physicochemical properties of drugs in addition to susceptibility of drugs to Phase I and Phase II metabolism enzymes. More 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)1-4). Numerous transporters have been identified with potential to mediate uptake and elimination processes in the intestine, liver, kidney and at the blood-brain barrier. While it is clear that transporters can influence major pathways regulating drug disposition, our current understanding of roles of specific transporters in drug disposition is limited to examples with isolated compounds. This is in part due to the overlapping substrate specificity for different transporters, and scarcity of specific substrates, inhibitors and biological models for studying the roles of specific transporters in vivo. One exception to this is the MDR1-gene product, P-glycoprotein (P-gp/ABCB1). In the past decade, the availability of in vitro 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 DDIs1, 3, 5, 6). P-gp appears to play a major role in the brain penetration of many compounds and also influence the pharmacokinetics and pharmacodynamics of several drugs. This is particularly true in the case of CNS-acting drugs in which P-gp has been shown to attenuate transport across the blood-brain barrier, thus limiting CNS exposure. 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 in vitro data be accurately extrapolated to the in vivo situation? (2) Can animal data be directly scaled up to humans? Application of in vitro drug transport studies to address clinically significant DDIs will also be presented.