Abstract：
: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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Masuda M,I'izuka Y,Yamazaki M,Nishigaki R,Kato Y,Ni'inuma K,Suzuki H,Sugiyama Ysubject
Has Abstractpub_date
1997-08-15 00:00:00pages
3506-10issue
16eissn
0008-5472issn
1538-7445journal_volume
57pub_type
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