RT Journal Article
SR Electronic
T1 Impact of Abcc2 (Mrp2), Abcc3 (Mrp3) and Abcg2 (Bcrp1) on the oral pharmacokinetics of methotrexate and its main metabolite 7-hydroxymethotrexate
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.111.038794
DO 10.1124/dmd.111.038794
A1 Maria LH Vlaming
A1 Anita van Esch
A1 Evita van de Steeg
A1 Zeliha Pala
A1 Els Wagenaar
A1 Olaf van Tellingen
A1 Alfred H. Schinkel
YR 2011
UL http://dmd.aspetjournals.org/content/early/2011/05/12/dmd.111.038794.abstract
AB The ATP-binding cassette (ABC) transporters ABCC2 (MRP2), ABCC3 (MRP3) and ABCG2 (BCRP) are involved in the efflux of potentially toxic compounds from the body. We have shown before that ABCC2, ABCC3 and ABCG2 together influence the pharmacokinetics of the anti-cancer and anti-rheumatic drug methotrexate (MTX) and its toxic metabolite 7-hydroxymethotrexate (7OH-MTX) after i.v. MTX administration. We now used Abcc2;Abcc3;Abcg2-/- and corresponding single and double knockout mice to investigate the relative impact of these transporters on MTX and 7OH-MTX pharmacokinetics after oral MTX administration (50 mg/kg). The plasma areas under the curve (AUCplasma) in Abcg2-/- and Abcc2;Abcg2-/- mice were 1.7- and 3.0-fold higher than in wild-type mice, respectively, suggesting additive effects of Abcc2 and Abcg2 on oral MTX pharmacokinetics. However, the AUCplasma in Abcc2;Abcc3;Abcg2-/- mice was not different from that in wild-type mice, indicating that Abcc3 protein is necessary for increased MTX plasma concentrations in the absence of Abcc2 and/or Abcg2. Furthermore, 2 h after administration, MTX liver levels were increased in Abcg2-deficient strains and MTX kidney levels were 2.2-fold increased compared to wild-type in Abcc2;Abcg2-/- mice. Absence of Abcc2 and/or Abcg2 also led to significantly increased liver and kidney levels of 7OH-MTX. Our results suggest that inhibition of ABCG2 and/or ABCC2, or genetic polymorphisms or mutations reducing expression or activity of these proteins may increase the oral availability of MTX. Such conditions may also present risk factors for increased MTX-related toxicity in patients treated with oral MTX.