Impaired clearance of methotrexate in organic anion transporter 3 (Slc22a8) knockout mice: a gender specific impact of reduced folates.

ABSTRACT:

Purpose

To elucidate the role of the renal basolateral transporter, Oat3, in the disposition of methotrexate.

Materials and methods

Chinese hamster ovary cells expressing mouse Oat3 were used to determine kinetics and specificity of inhibition of methotrexate transport. Methotrexate clearance was then examined in vivo in wildtype and Oat3 knockout mice.

Results

NSAIDs, beta-lactams, and uremic toxins inhibited mOat3-mediated methotrexate uptake by 70-100%, while folate, leucovorin, and 5-methyltetrahydrofolate inhibited transport by 25-50%. A Km of 60.6 +/- 9.3 microM for methotrexate transport was determined. Oat3 knockout mice exhibited reduced methotrexate-to-inulin clearance ratios versus wildtype. Male wildtype mice, but not knockouts or females, demonstrated sig

SUBMITTER: VanWert AL 

PROVIDER: S-EPMC2820254 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature