Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats.
Methotrexate [(+) amethopterin, L-MTX] has two carboxyl groups in its structure and is eliminated mainly by excretion into urine and bile. To investigate the biliary excretion mechanism of L-MTX, we performed in vivo and in vitro studies using mutant rats, Eisai hyperbilirubinemic rats (EHBRs), whose canalicular multispecific organic anion transporter (cMOAT) is defective as a consequence of heredity. After i.v. administration of L-MTX to EHBRs, its plasma disappearance and biliary excretion was slower than in normal Sprague Dawley rat (SDR). ATP-dependence and overshoot phenomena were observed in the uptake of [3H]L-MTX by canalicular membrane vesicles (CMV) prepared from SDR, whereas no ATP-dependence was observed in CMV from EHBRs. The ATP-dependent uptake of L-MTX by SDR CMV exhibited saturable kinetics with a Km of 295 microM. L-MTX competitively inhibited the ATP-dependent uptake of [3H]2,4-dinitrophenyl-S-glutathione, a typical substrate for cMOAT, and the inhibition constant (Ki) of L-MTX was comparable with its own Km. These results suggest that L-MTX is excreted into bile by cMOAT. The inhibitory effects of L-MTX and its optical isomer, (-) amethopterin (D-MTX), on the uptake of [3H]L-MTX differed with Kis of 326 and 93 microM, respectively, indicating that the biologically inactive D form has a higher affinity for cMOAT than L-MTX.[1]References
- Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats. Masuda, M., I'izuka, Y., Yamazaki, M., Nishigaki, R., Kato, Y., Ni'inuma, K., Suzuki, H., Sugiyama, Y. Cancer Res. (1997) [Pubmed]
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