Molecular basis for quantitative prediction of drug-drug interaction at excretion process

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Recent progress in molecular biology has revealed predominant roles of many types of xenobiotic transporters in drug secretion into the urine and bile, leading to possible occurrence of drug-drug interaction at the excretion processes. Therefore, it is expected to predict the interaction based on in vitro experimental system. This study aimed to clarify molecular basis for the prediction of drug-drug interaction at the excretion process in liver and kidney. As model drugs that are excreted into the bile and urine, a novel uric acid generation inhibitor Y-700 and a novel diuretic M17055 were used. We have suggested involvement of Na^+-dependent organic anion transport system, other than OATP family, in hepatic uptake of Y-700, part of Y-700 uptake being mediated by bile acid transporter NTCP. We have also clarified important role of OAT1 in renal uptake of M17055. Furthermore, we have identified direct interaction of certain types of transporters, that are expressed on apical membranes in kidney and/or small intestine, with PDZ domain containing proteins PDZK family, implying that such protein-protein interaction may play a role in apical localization of the transporters. Among the PDZ proteins, PDZK1 is colocalized on apical membranes in kidney and small intestine with OCTN2, and can stimulate transport activity of several transporters including OCTN1, OCTN2 and PEPT2. Finally, we have focused on functional modulation of oligopeptide transporter PEPT1 by Na^+/H^+ exchanger (NHE) 3 that can also bind to the PDZ proteins and supply H^+ gradient that can be utilized by PEPT1 for transport activity. NHE3 affects transport activity, Na^+- and H^+- dependence of PEPT1. Thus, this study has proposed a novel concept that adaptor proteins (such as PDZK1) and other membrane proteins (such as NHE3), both having interaction potential with transporters, could be important molecular basis for prediction of drug-drug interaction at excretion processes.