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

MLH Vlaming, Z Pala, A van Esch, E Wagenaar… - Clinical Cancer …, 2008 - AACR
MLH Vlaming, Z Pala, A van Esch, E Wagenaar, O van Tellingen, DR de Waart…
Clinical Cancer Research, 2008AACR
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 …
Abstract
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 (AUCi.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 AUCi.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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