Changes in absorptive function of rat intestine injured by methotrexate.
1. Methotrexate (MTX), an anticancer drug, has been shown to induce acute injury in the small intestine. The present study was designed to investigate the in vivo absorptive function of the small intestine injured by MTX using an amino-beta-lactam antibiotic cephalexin (CEX). Time-dependent changes in diamine oxidase (DAO) and alkaline phosphatase (ALP) activity in the small intestine and histopathological findings were also measured in rats treated with MTX (20 mg/kg). 2. Most severe mucosal damage was observed 2 days after MTX treatment and the area under the plasma concentration-time curve of CEX (AUC(CEX)) following oral administration of 20 mg/kg tended to decrease. Thereafter, the AUC(CEX) increased significantly and the histopathological changes diminished within 5 days. 3. Both villus height and mucosal weight followed the same pattern, decreasing in the first 2 or 3 days following treatment, increasing on the 5th day and returning to control levels by the 10th day. Methotrexate-induced changes in the mucosal wet weight/whole intestinal weight ratio were significantly correlated with those of AUC(CEX), but did not correlate with mucosal DAO and ALP activity. 4. These findings provide evidence that the change in the total amount of CEX is an index of the active transport function, probably by intestinal peptide transporter (PEPT1), and is well reflected by histopathological changes in the intestinal mucosa induced by MTX. In addition, there is a possibility that this method could be applied in the clinical setting for diagnosis of intestinal status and absorptive function.
Naruhashi
K
K
Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Nadai
M
M
Nakao
M
M
Suzuki
N
N
Nabeshima
T
T
Hasegawa
T
T
D000469:Alkaline Phosphatase / Q000378:metabolism; D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D015820:Cadherins; D002352:Carrier Proteins / Q000378:metabolism; D002506:Cephalexin / Q000378:metabolism*; D002511:Cephalosporins / Q000378:metabolism*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins; D008727:Methotrexate / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar
D000964:Antimetabolites, Antineoplastic; D015820:Cadherins; D002352:Carrier Proteins; C490586:Cdh17 protein, rat; D002511:Cephalosporins; D026901:Membrane Transport Proteins; C067802:intestinal peptide-proton cotransporter; D006631:Amine Oxidase (Copper-Containing); D000469:Alkaline Phosphatase; D002506:Cephalexin; D008727:Methotrexate