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Impact of Abcc2 (Mrp2) and Abcc3 (Mrp3) on the In vivo Elimination of Methotrexate and its Main Toxic Metabolite 7-hydroxymethotrexate

Authors' Affiliations: ¹ Divisions of Experimental Therapy, ² Clinical Chemistry, and ³ Molecular Biology, The Netherlands Cancer Institute and ⁴ AMC Liver Center, Academic Medical Center, Amsterdam, the Netherlands and ⁵ Faculty of Pharmacy, Istanbul University, Istanbul, Turkey

Requests for reprints: Alfred H. Schinkel, Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands. Phone: 31-20-512-2046; Fax: 31-20-512-2050; E-mail: a.schinkel{at}nki.nl.

Purpose: ATP-binding cassette sub-family C member 2 [ABCC2; multidrug resistance–associated protein 2 (MRP2)] and ABCC3 (MRP3) mediate the elimination of toxic compounds, such as drugs and carcinogens, and have a large overlap in substrate specificity. We investigated the roles of Abcc2 and Abcc3 in the elimination of the anticancer drug methotrexate (MTX) and its toxic metabolite 7-hydroxymethotrexate (7OH-MTX) in vivo.

Experimental Design: Abcc2;Abcc3^–/– mice were generated, characterized, and used to investigate possibly overlapping or complementary roles of Abcc2 and Abcc3 in the elimination of MTX and 7OH-MTX after i.v. administration of 50 mg/kg MTX.

Results: Abcc2;Abcc3^–/– mice were viable and fertile. In Abcc2^–/– mice, the plasma area under the curve (AUC_i.v.) for MTX was 2.0-fold increased compared with wild type, leading to 1.6-fold increased urinary excretion, which was not seen in Abcc2;Abcc3^–/– mice. Biliary excretion of MTX was 3.7-fold reduced in Abcc2^–/– but unchanged in Abcc2;Abcc3^–/– mice. The plasma AUC_i.v.s of 7OH-MTX were 6.0-fold and 4.3-fold increased in Abcc2^–/– and Abcc2;Abcc3^–/– mice, respectively, leading to increased urinary excretion. The biliary excretion of 7OH-MTX was 5.8-fold reduced in Abcc2^–/– but unchanged in Abcc2;Abcc3^–/– mice. 7OH-MTX accumulated substantially in the liver of Abcc2^–/– and especially Abcc2;Abcc3^–/– mice.

Conclusions: Abcc2 is important for (biliary) excretion of MTX and its toxic metabolite 7OH-MTX. When Abcc2 is absent, Abcc3 transports MTX and 7OH-MTX back from the liver into the circulation, leading to increased plasma levels and urinary excretion. Variation in ABCC2 and/or ABCC3 activity may therefore have profound effects on the elimination and severity of toxicity of MTX and 7OH-MTX after MTX treatment of patients.

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				M. L.H. Vlaming, Z. Pala, A. van Esch, E. Wagenaar, D. R. de Waart, K. van de Wetering, C. M.M. van der Kruijssen, R. P.J. Oude Elferink, O. van Tellingen, and A. H. Schinkel Functionally Overlapping Roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the Elimination of Methotrexate and Its Main Toxic Metabolite 7-Hydroxymethotrexate In vivo Clin. Cancer Res., May 1, 2009; 15(9): 3084 - 3093. [Abstract] [Full Text] [PDF]