Protective effect of a synthetic analog of prostaglandin E(1) on the small intestinal damage induced by the administration of methotrexate to rats.
Antitumor drugs like methotrexate cause damage to the small intestine, resulting in malabsorption. The present study evaluated this damage by determining the small intestinal absorption of 3-O-methyl-D-glucose (3-OMG) and a poorly absorbable marker, fluorescein isothiocyanate-labeled dextran (FD-4; average molecular mass, 4.4 KDa) using the in vitro everted intestine and in situ intestinal loop techniques. Methotrexate (15 mg/kg body weight) was orally administered to rats once daily for 5 days. A synthetic analog of prostaglandin E(1), OP-1206 (17S,20-dimethyl-trans-Delta(2)-prostaglandin E(1); 0.5 microg/kg body weight) was orally administered to rats twice a day for 5 days. The absorption clearance of FD-4 via the small intestine of the methotrexate-treated rats increased marked, but that of the methotrexate- and OP-1206-treated rats was significantly lower than that of the rats treated only with methotrexate. The absorption clearance of [(3)H]-3-OMG via the small intestine of the methotrexate-treated rats fell markedly, but that of the methotrexate- and OP-1206-treated rats was significantly greater than that of the rats treated only with methotrexate. The changes in AUC values of FD-4 and [(3)H]-3-OMG obtained from in situ intestinal loop experiment showed the same trends as those seen in the absorption clearance from the in vitro everted intestine experiment. These results show that OP-1206 alleviates the methotrexate-induced damage to the small intestine of rats.
Gao
F
F
Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
Nakamaru
M
M
Masubuchi
Y
Y
Horie
T
T
D019325:3-O-Methylglucose / Q000493:pharmacokinetics; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar
D019325:3-O-Methylglucose; D000527:Alprostadil; D008727:Methotrexate