Methotrexate Is Excreted into the Bile by Canalicular Multispecific Organic Anion Transporter in Rats

摘要: Methotrexate [(+) amethopterin, L-MTX] has two carboxyl groups in its structure and is eliminated mainly by excretion into urine bile. To investigate the biliary mechanism of L-MTX, we performed vivo vitro studies using mutant rats, Eisai hyperbilirubinemic rats (EHBRs), whose canalicular multispecific organic anion transporter (cMOAT) defective as a consequence heredity. After i.v. administration L-MTX to EHBRs, plasma disappearance was slower than normal Sprague Dawley rat (SDR). ATP-dependence overshoot phenomena were observed uptake [3H]L-MTX membrane vesicles (CMV) prepared from SDR, whereas no CMV EHBRs. The ATP-dependent SDR exhibited saturable kinetics with K m 295 µm. competitively inhibited [3H]2,4-dinitrophenyl- S -glutathione, typical substrate for cMOAT, inhibition constant ( i) comparable own m. These results suggest that excreted bile cMOAT. inhibitory effects optical isomer, (-) amethopterin (D-MTX), on differed 326 93 µm, respectively, indicating biologically inactive D form higher affinity cMOAT L-MTX.