Increasing systemic exposure of methotrexate by active efflux mediated by multidrug resistance-associated protein 3 (mrp3/abcc3).
The aim of this study was to investigate the functional importance of multidrug resistance-associated protein (Mrp)3/Abcc3 and Mrp4/Abcc4 in the pharmacokinetics of methotrexate. Compared with the corresponding wild-type mice, the plasma concentrations of methotrexate given orally were similar in Abcc4(-/-) mice and were significantly lower in Abcc3(-/-) mice. Pharmacokinetic parameters related to hepatobiliary transport were determined under steady-state conditions in wild-type and Abcc3(-/-) mice that were given a constant intravenous infusion of methotrexate. The biliary clearance, based on the plasma concentration, was 1.6-fold greater in Abcc3(-/-) mice than in wild-type mice (23 and 15 ml/min/kg, respectively, P < 0.05). Because the basolateral uptake and canalicular efflux clearances of methotrexate were similar in wild-type and Abcc3(-/-) mice, this result suggests that the basolateral efflux clearance of methotrexate is decreased in the liver of Abcc3(-/-) mice. Furthermore, a lower fraction of absorption of methotrexate (F(a) F(g)) was suggested in Abcc3(-/-) mice (0.49 and 0.29 in wild-type and Abcc3(-/-) mice, respectively). The mucosal-to-serosal transport rate of methotrexate, determined in vitro using everted sacs, was highest in the duodenum and was significantly decreased in Abcc3(-/-) mice compared with wild-type mice. This is ascribed to the reduced intrinsic efflux clearance of methotrexate across the serosal membrane (22 and 5.3 mul/min/sac in wild-type and Abcc3(-/-) mice, respectively, P < 0.05). These results suggest that Mrp3 mediates basolateral efflux of methotrexate in the liver and duodenum, thereby serving to increase systemic exposure, whereas Mrp4 is likely to play only a limited role in the systemic methotrexate exposure.
Kitamura
Yoshiaki
Y
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Hirouchi
Masakazu
M
Kusuhara
Hiroyuki
H
Schuetz
John D
JD
Sugiyama
Yuichi
Y
D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics; D058973:Folate Receptors, GPI-Anchored; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000235:genetics
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C489540:Abcc4 protein, mouse; C114462:multidrug resistance-associated protein 3