Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate

Author： Kato Sayaka Ito Katsuaki Kato Yukio Wakayama Tomohiko Kubo Yoshiyuki Iseki Shoichi Tsuji Akira

ISSN： 0724-8741

Source： Pharmaceutical Research, Vol.26, Iss.6, 2009-06, pp. : 1467-1476

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Abstract

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.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.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.Mrp1 determines the exposure of proliferative cells in the small intestine to MTX, followed by gastrointestinal toxicity.