QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.140475v1 327/2/465    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kitamura, Y. Articles by Sugiyama, Y. Search for Related Content PubMed PubMed Citation Articles by Kitamura, Y. Articles by Sugiyama, Y.

METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Increasing Systemic Exposure of Methotrexate by Active Efflux Mediated by Multidrug Resistance-Associated Protein 3 (Mrp3/Abcc3)

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (Y.K., M.H., H.K., Y.S.); and Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (J.D.S.)

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 µl/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.

Address correspondence to: Dr. Hiroyuki Kusuhara, Associate Professor, Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. E-mail: kusuhara{at}mol.f.u-tokyo.ac.jp

This article has been cited by other articles:

				T. Watanabe, K. Maeda, T. Kondo, H. Nakayama, S. Horita, H. Kusuhara, and Y. Sugiyama Prediction of the Hepatic and Renal Clearance of Transporter Substrates in Rats Using in Vitro Uptake Experiments Drug Metab. Dispos., July 1, 2009; 37(7): 1471 - 1479. [Abstract] [Full Text] [PDF]