Abstract
Purpose
Methotrexate (MTX) causes dose-limiting gastrointestinal toxicity due to exposure of intestinal tissues, and is a substrate of the multidrug resistance-associated protein (MRP) 1. Here we examine the involvement of MRP1, which is reported to be highly expressed in the proliferative crypt compartment of the small intestine, in the gastrointestinal toxicity of MTX.
Methods
MTX was intraperitonealy administered to mrp1 gene knockout (mrp1 (−/−)) and wild-type (mrp1 (+/+)) mice. Body weight, food and water intake were monitored, intestinal histological studies and pharmacokinetics of MTX were examined.
Results
mrp1 (−/−) mice more severely decreased body weight, food and water intake than mrp1 (+/+) mice. Almost complete loss of villi throughout the small intestine in mrp1 (−/−) mice was observed, whereas the damage was only partial in mrp1 (+/+) mice. Plasma concentration and biliary excretion profiles of MTX were similar in mrp1 (−/−) and mrp1 (+/+) mice, though accumulation of MTX in immature proliferative cells isolated from mrp1 (−/−) mice was much higher compared to mrp1 (+/+) mice. Immunostaining revealed localization of Mrp1 in plasma membrane of the intestinal crypt compartment in mrp1 (+/+) mice, but not in mrp1 (−/−) mice.
Conclusion
Mrp1 determines the exposure of proliferative cells in the small intestine to MTX, followed by gastrointestinal toxicity.
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Acknowledgement
We thank Ms. Lica Ishida and Mr. Syuichi Yamazaki for technical assistance. This work was supported in part by a Grant-in-Aid for Scientific Research provided by the Ministry of Education, Science and Culture of Japan and funds from the Kanehara Grant Program 2004 of the Ichiro Kanehara Foundation (Tokyo, Japan).
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Kato, S., Ito, K., Kato, Y. et al. Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate. Pharm Res 26, 1467–1476 (2009). https://doi.org/10.1007/s11095-009-9858-6
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DOI: https://doi.org/10.1007/s11095-009-9858-6