Abstract
Methotrexate (MTX) is a substrate for numerous human ATP-binding cassette (ABC) efflux transporters, yet the impact of these transporters on MTX pharmacokinetics (PK) over a large dose range has not been examined. To investigate the effects of two transporters—ABC subfamily C member 2 (Abcc2; multidrug resistance protein 2) and ABC subfamily C member 3 (Abcc3; multidrug resistance protein 3)—involved in MTX hepatobiliary disposition in vivo, MTX plasma, urine, and feces concentrations were analyzed after 10, 50, and 200 mg/kg i.v. doses to groups of wild type (WT), Abcc2(−/−), and Abcc3(−/−) mice. The absence of Abcc2 caused a decrease in total clearance of MTX relative to WT mice at all dose levels yet was accompanied by compensatory increases in renal excretion and metabolism to 7-hydroxymethotrexate (7OH-MTX). In Abcc3(−/−) mice, total clearance was elevated at the two lower dose levels and was attributed to stimulation of biliary excretion and confirmed by elevated fecal excretion; however, at the high 200 mg/kg dose, clearance was severely retarded and could be attributed to hepatotoxicity because conversion to 7OH-MTX was diminished. The findings confirmed that both Abcc2 and Abcc3 significantly influenced the PK properties of MTX, and depending on the MTX dose and strain, alternate elimination pathways were elicited and saturable.
Footnotes
This work was supported by the National Institutes of Health National Cancer Institute [Grant CA114574].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.041228.
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ABBREVIATIONS:
- ABC
- ATP-binding cassette
- ABCC2
- ABC subfamily C member 2
- ABCC3
- ABC subfamily C member 3
- ANOVA
- analysis of variance
- AUC
- area under the concentration-time curve
- CL
- total systemic clearance
- ff
- fecal fraction of dose
- fu
- renal fraction of dose
- IV
- intravenous
- LC/MS/MS
- liquid chromatography/tandem mass spectrometry
- MRP
- multidrug resistance proteins
- MTX
- methotrexate
- 7OH-MTX
- 7-hydroxymethotrexate
- PK
- pharmacokinetic
- Vd
- volume of distribution
- WT
- wild type.
- Received June 16, 2011.
- Accepted August 8, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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