Species differences of organic anion transporters involved in the renal uptake of 4-amino-3-chlorophenyl hydrogen sulfate, a metabolite of resatorvid, between rats and dogs

ABSTRACT Previous studies on the metabolic fate of resatorvid (TAK‐242) have shown that species differences in the pharmacokinetics of 4‐amino‐3‐chlorophenyl hydrogen sulfate (M‐III), a metabolite of TAK‐242, between rats and dogs are mainly attributable to the urinary excretion process. In the present study, the renal uptake mechanism of M‐III was investigated using kidney slices and Xenopus laevis oocytes expressing rat organic anion transporter 1 (rOat1; Slc22a6) and rOat3 (Slc22a8). The uptake of p‐aminohippuric acid (PAH), a substrate for Oats, by kidney slices from rats and dogs increased at 37 °C and M‐III inhibited the uptake. The initial uptake clearance of M‐III by rat kidney slices was 0.295 and 0.0114 ml/min/g at 37 °C and 4 °C, respectively. The Eadie‐Hofstee plot of M‐III uptake at 37 °C revealed two‐component transport processes with Km values being 6.48 and 724 µmol/l. The uptake was inhibited by probenecid (PBC), PAH and benzylpenicillin (PCG). In contrast, in dog kidney slices, the initial uptake clearance of M‐III was 8.70 × 10‐3 and 9.00 × 10‐3 ml/min/g at 37 °C and 4 °C, respectively, and the uptake was not inhibited by PBC. Furthermore, rOat1‐ and rOat3‐expressing oocytes mediated M‐III uptake and the uptake was inhibited by PAH and PCG, respectively. These results suggest that rOat1 and rOat3 are responsible for the renal uptake of M‐III in rats. Moreover, it is speculated that Oat(s) is unable to transport M‐III in dogs and that the difference in the substrate recognition of Oat(s) contributes to the species difference in the pharmacokinetics of M‐III between rats and dogs. Copyright © 2013 John Wiley & Sons, Ltd.