title: 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 K(m) 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.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, Japan. Takeuchi_ Toshiyuki@takeda.co.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Jinno
authors.forename: Takuya
authors.initials: T
authors.lastname: Ebihara
authors.forename: Yuu
authors.initials: Y
authors.lastname: Moriya
authors.forename: Rie
authors.initials: R
authors.lastname: Kadotani
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tagawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kondo
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.forename: Satoru
authors.initials: S
authors.lastname: Asahi
mesh_terms: D000814:Aniline Compounds / Q000493:pharmacokinetics*; D000818:Animals; D001557:Benzenesulfonates / Q000493:pharmacokinetics*; D001692:Biological Transport; D004285:Dogs; D005260:Female; D007668:Kidney / Q000378:metabolism*; D008297:Male; D009865:Oocytes; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D010400:Penicillin G / Q000494:pharmacology; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013696:Temperature; D014982:Xenopus laevis
chemical_list: C574025:4-amino-3-chlorophenyl hydrogen sulfate; D000814:Aniline Compounds; D001557:Benzenesulfonates; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C421043:Slc22a6 protein, rat; C114338:organic anion transport protein 3; D011339:Probenecid; D010400:Penicillin G