Impaired Clearance of Methotrexate in Organic Anion Transporter 3 (Slc22a8) Knockout Mice: A Gender Specific Impact of Reduced Folates

Authors

Adam L. VanWert, Medical University of South Carolina
Douglas H. Sweet, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2008

Journal/Book/Conference Title

Pharmaceutical Research

Volume

25

Issue

2

First Page

453

Last Page

462

DOI of Original Publication

10.1007/s11095-007-9407-0

Comments

The final publication is available at Springer via http://dx.doi.org/10.1007/s11095-007-9407-0.

Douglas H. Sweet was at Medical University of South Carolina at the time of publication.

Date of Submission

October 2015

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, ß-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 μM 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 significantly accelerated methotrexate clearance in response to reduced folates. Reduced folates also markedly inhibited hepatic methotrexate accumulation in males, but not females, and the response was independent of Oat3 function.

Conclusions

Oat3 contributes to methotrexate clearance, but represents only one component responsible for methotrexate's elimination. Therefore, in patients, dysfunctional hOAT3 polymorphisms or drug competition for hOAT3 transport may severely impact methotrexate elimination only when redundant means of methotrexate removal are also compromised. Furthermore, the present findings suggest that reduced-folate administration only influences methotrexate disposition in males, with the renal reduced-folate response influenced by OAT3 function.

Rights

Copyright © 2007, Springer Science+Business Media, LLC. This is the author’s manuscript of a work that was accepted for publication in Pharm Res. 2008 Feb; 25(2):453-462. The final publication is available at Springer via http://dx.doi.org/10.1007/s11095-007-9407-0

Is Part Of

VCU Pharmaceutics Publications