Controversy exists as to whether administration of a chemically defined diet alters toxicity to chemotherapy. The purpose of this study was to evaluate toxicity to methotrexate in rats fed a chemically defined liquid diet or a regular chow diet. In the first study, 48 adult rats were randomized to be fed a chemically defined liquid diet or a regular diet for 14 days when methotrexate (25 or 50 mg/kg) was given. All liquid diet rats became anorexic and died within 96 h, while no deaths were observed in rats fed regular diet. When 20 liquid diet and regular diet rats were pair-fed to equalize caloric intake before and after methotrexate administration, similar mortality results occurred. In a second study, methotrexate (50 mg/kg) or saline was given and 60 h later all animals were sacrificed to obtain small bowel luminal cultures and tissue sections for histological evaluation. Administration of the liquid diet altered small bowel flora to predominantly Escherichia coli and Pseudomonas sp. and histology showed severe small bowel mucosal enteritis in comparison with regular diet rats. To evaluate whether the changes in intestinal flora or alterations in drug pharmacokinetics were responsible for the increased mortality, two additional studies were done. Gentamicin (4.8 mg/kg/day) was given p.o. or i.m. to the rats on the chemically defined liquid diet. A significant reduction of intraluminal bacteria occurred, but survival time was not improved in animals receiving antibiotics. When mean serum methotrexate levels were analyzed in non-antibiotic-treated rats, drug concentrations were significantly increased at 24, 36, and 48 h after methotrexate injection in the elemental liquid diet rats compared with chow diet rats. Administration of a chemically defined liquid diet to rats receiving methotrexate increased the occurrence and severity of intestinal enteritis, altered intraluminal bowel flora, and decreased clearance of methotrexate from the serum.

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