Abstract
OATP4C1 is an organic anion transporter expressed in the basolateral membrane of the renal proximal tubules. It plays a major role in the urinary excretion of both exogenous drugs and endogenous compounds. Our previous studies have indicated the importance of OATP4C1 in pathological and physiological conditions; however, the majority of its pharmacological characteristics remained unclear. Therefore, to provide essential information for clinical drug therapy decisions and drug development, we, in this study, attempted to clarify drug interactions mediated by OATP4C1. To elucidate potential drug interactions via OATP4C1, we screened 53 representative drugs, which are commonly used in clinical settings. Next, we evaluated IC50 values of drugs which inhibited OATP4C1 by more than 50%. To apply our results to clinical settings, we calculated the drug-drug interaction (DDI) indices. The screening analysis using an OATP4C1-expressing cell system demonstrated that 22 out of 53 therapeutic drugs inhibited OATP4C1-mediated T3 transport. In particular, OATP4C1-mediated transport was strongly inhibited by 10 drugs. The IC50 values of 10 drugs; nicardipine, spironolactone, fluvastatin, crizotinib, levofloxacin, clarithromycin, ritonavir, saquinavir, quinidine, and verapamil, obtained in this study were 51, 53, 41, 24, 420, 200, 8.5, 4.3, 100, and 110 µM, respectively. The IC50 values of these drugs were higher than plasma concentrations obtained in clinical practice. However, ritonavir showed the highest DDI index (1.9) for OATP4C1, suggesting that it may strongly influence this transporter and thus cause drug interactions that are seen in clinical settings. Our finding gives new insight into the role of OATP4C1 in clinical DDIs.
- The American Society for Pharmacology and Experimental Therapeutics