Document Detail


Impaired clearance of methotrexate in organic anion transporter 3 (Slc22a8) knockout mice: a gender specific impact of reduced folates.
MedLine Citation:
PMID:  17660957     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 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.
Authors:
Adam L VanWert; Douglas H Sweet
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-07-28
Journal Detail:
Title:  Pharmaceutical research     Volume:  25     ISSN:  0724-8741     ISO Abbreviation:  Pharm. Res.     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-02-18     Completed Date:  2008-04-22     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  453-62     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
CHO Cells
Cricetinae
Cricetulus
Female
Folic Acid / metabolism*
Kidney / metabolism
Male
Metabolic Clearance Rate
Methotrexate / pharmacokinetics*
Mice
Mice, Knockout
Organic Anion Transporters, Sodium-Independent / physiology*
Sex Characteristics
Grant Support
ID/Acronym/Agency:
C06 RR015455/RR/NCRR NIH HHS; R01 DK067216/DK/NIDDK NIH HHS; R01 DK067216-04/DK/NIDDK NIH HHS; R01DK-067216/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Organic Anion Transporters, Sodium-Independent; 0/organic anion transport protein 3; 935E97BOY8/Folic Acid; YL5FZ2Y5U1/Methotrexate
Comments/Corrections

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