Our long-range goal is to determine the factors that contribute to inter-patient variability and drug-drug interactions as a way to maximize drug delivery and minimize drug toxicity. The objective of this application, which is the next step in pursuit of that goal, is to develop a model to characterize the role of drug transporters in an in vitro kidney model (HK-2) that may be used as part of an in vitro/in vivo correlation (IVIVC) model of renal drug transport. The main research questions are: 1) Can an in vitro model be used to describe drug transport for the probes cimetidine and PAH, 2) Does a correlation exist between drug transport rate in vitro and renal drug clearance in vivo?, and 3) Does the presence of a genetic variant (MDR1 SNP) describe variability in renal drug clearance? This project has important clinical implications since a predictive model could be used to screen new drugs that may undergo extensive renal tubular secretion and be susceptible to competitive drug interactions within the kidney. The rationale for the proposed research is that development of a validated IVIVC model of renal drug elimination will lead to new dosing strategies with a goal of avoiding drug interactions and reducing drug-related toxicity. We plan to test our hypothesis and accomplish the objectives of this application by pursuing the following specific aims: 1) evaluate the transcellular transport of cimetidine and PAH in vitro using a human-derived proximal tubule cell line (HK-2), 2) determine the relationship between in vitro transport rates and in vivo tubular secretion of cimetine and PAH in humans, 3) determine the frequency of genetic variant (MDR-SNP) and its relationship to drug clearance. An innovative translational research approach will be used in this study of renal drug transport. The successful completion of this research will allow us to identify the relationships between in vitro and in vivo observations relating to renal drug clearance, and it is our expectation that this project will provide significant new information regarding evaluation of IVIVC models using HK-2 cells.
