Abstract
Organic anion-transporting polypeptides (OATPs) are key transporters of hepatic uptake for endogenous compounds and xenobiotics. Human OATP1B1 and OATP1B3 are well-studied due to their role in drug-drug interactions. In contrast, data on murine OATP1B2, the rodent orthologue of these transporters, are limited, despite its importance in early drug development. Here, we systematically compared the transport characteristics of mouse and rat OATP1B2 under identical experimental conditions. The K(m) values for estrone-3-sulfate (E(1)S) and taurocholate (TCA) were 242 and 73 µM for mOATP1B2 and 90 and 16 µM for rOATP1B2. Nine clinically relevant drugs were evaluated for inhibitory effects, showing strong correlation between species. Cyclosporine A, ritonavir, odevixibat, rosuvastatin, and rifampicin markedly inhibited uptake. Rifampicin demonstrated species-specific differences, with higher IC(50) values for mOATP1B2 (E(1)S: 9.6 µM; TCA: 7.7 µM) than rOATP1B2 (E(1)S: 1.1 µM; TCA: 2.4 µM). A comparison of the rodent data with the human orthologues revealed similar inhibition patterns but distinct substrate selectivity: hOATP1B1 showed high affinity for E(1)S but negligible TCA uptake, while hOATP1B3 transported TCA weakly but not E(1)S. This study provides insights into species-specific differences in OATP-mediated hepatic uptake and is therefore valuable for the interpretation of preclinical studies and their transfer to human pharmacology.