Potential Drug Interactions Mediated by Renal Organic Anion Transporter OATP4C1

Abstract

Organic anion-transporting polypeptide 4C1 (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 pathologic and physiologic conditions; however, the majority of its pharmacologic characteristics remained unclear. Therefore, to provide essential information for clinical drug therapy decisions and drug development, we clarified drug interactions mediated by OATP4C1. To elucidate potential drug interactions via OATP4C1, we screened 53 representative drugs commonly used in clinical settings. Next, we evaluated the IC values of drugs that 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 triiodothyronine transport. In particular, OATP4C1-mediated transport was strongly inhibited by 10 drugs. The IC 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 M, respectively. The IC values of these drugs were higher than the 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 seen in clinical settings. Our finding gives new insight into the role of OATP4C1 in clinical DDIs.

Impact of rifampicin-inhibitable transport on the liver distribution and tissue kinetics of erlotinib assessed with PET imaging in rats

“…Erlotinib is also a substrate of OCT2 which is not inhibited by rifampicin [ 12 , 27 ]. Rifampicin is not an inhibitor of OATP4C1 [ 34 ] which importance for erlotinib transport is not known. Previous mice studies have shown that parent unmetabolized 11 C-erlotinib could not be detected in urines [ 14 ].…”

Effects of proton pump inhibitors and famotidine on elimination of plasma methotrexate: Evaluation of drug–drug interactions mediated by organic anion transporter 3

“…OATP4C1 is also localized at the basolateral membranes of proximal tubule cells, and has been shown to transport MTX (Mikkaichi et al, ). A recent study found that lansoprazole (100 μ m ) and rabeprazole (100 μ m ) caused no inhibition of OATP4C1‐mediated transport of triiodothyronine (Sato, Mishima, Mano, Abe, & Yamaguchi, ). These findings suggest that OATP4C1 is not responsible for the PPI–MTX interaction.…”

Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance

“…OATP4C1 has been challenging to study due to the inconsistent ability to attain functional expression in vitro . A recent OATP4C1 in vitro inhibition screening of 53 drugs only identified ritonavir as a clinically relevant inhibitor . An unexpected DDI between bupropion and digoxin was reported, where bupropion increased renal clearance of digoxin by 80% .…”