Functional characterization and comparison of human and mouse organic anion transporter 1 as drugs and pesticides uptake carrier.

ABSTRACT

The organic anion transporter 1 (OAT1) is mainly expressed in proximal tubule cells, where it mediates the renal uptake of endogenous and exogenous compounds. Thereby, it has enormous clinical relevance particularly in drug-drug interactions. The aim of the present in vitro study was to elucidate potential species dependent disparity of human and mouse OAT1 in handling of structural diverse drugs and pesticides. A basic functional comparison of the two transporters showed a similar time-dependent uptake of the substrate para-aminohippuric acid (PAH), the affinity (Km) was 94 µM for hOAT1 and 32 µM for mOat1. Inhibition experiments for hOAT1 and mOat1 provided IC50 values for glibenclamide of 5.1 and 6.4 µM and for probenecid of 31 and 11 µM. Than the interaction of hOAT1 and mOat1 with 23 drugs and 13 pesticides was examined. Three pesticides and thirteen drugs showed high inhibitory potency of 50% or more to both transporters. Furthermore, we identified rosiglitazone as a differential active inhibitor, with stronger inhibitory properties (IC50) to mOat1 (7.7 µM) than to hOAT1 (31 µM), and olmesartan with the most pronounced difference The IC50 of hOAT1 (0.40 µM) was 48-fold lower than of mOat1 (19 µM). In conclusion, we found a strong correlation for the inhibitory effects of most drugs and pesticides on human and mouse OAT1. But the example of olmesartan shows that species differences have to be considered when extrapolating data from mouse to human.