Abstract
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 (Fa Fg) 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.
Footnotes
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This study was supported by a grant-in-aid for Scientific Research (A) from Japan Society for the Promotion of Science (JSPS) (KAKENHI 17209005; to Y.S.) and a grant-in-aid for Scientific Research (B) from JSPS (KAKENHI 18390046; to H.K.).
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Y.K. and M.H. contributed equally to this study.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.140475.
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ABBREVIATIONS: MRP/Mrp, multidrug resistance-associated protein; ABC/Abc, ATP-binding cassette; PCFT/Pcft, proton-coupled folate transporter; RFC/Rfc, reduced folate carrier; OAT/Oat, organic anion transporter; BCRP/Bcrp, breast cancer resistance protein; G3pdh, glyceraldehyde-3-phosphate dehydrogenase; PCR, polymerase chain reaction; OATP, organic anion transporting polypeptide.
- Received April 28, 2008.
- Accepted July 14, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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