Alteration of methotrexate toxicity in rats by manipulation of dietary components

Administration of a chemically defined, elemental diet to rats given 20 mg/kg of methotrexate intraperitoneally has consistently resulted in a 100% mortality from severe enteritis within 156 h. This study examined the importance of specific dietary components in the etiology of this enhanced toxicity. Rats were given their respective diets for 7 days, whereupon methotrexate (20 mg/kg) was given intraperitoneally, and percent of survivors was recorded. Varying the concentration of carbohydrate as polysaccharide (0%, 50%, 100%) (n = 30) had no effect on survival. An increase in the percent of protein as polypeptide (0%, 25%, 50%, 75%, 100%) (n = 50) in the elemental diet resulted in a progressively significant increase in percent survival. Addition of either fat or bulk to this elemental diet had no effect on survivorship. Serum and bile methotrexate levels of rats fed an elemental liquid diet (whether or not all of the protein was provided as polypeptide) were significantly increased from 12 to 72 h (p less than 0.03) compared with rats fed a regular Chow diet. When the protein content of the elemental liquid diet was provided as 100% polypeptide, serum and bile methotrexate levels were significantly lower at 48 h compared with the elemental diet group given 100% of protein as amino acid. Administration of methotrexate to rats fed an elemental liquid diet in which all of the protein is provided as amino acids is extremely toxic to the gastrointestinal tract, probably as a result of delayed clearance of the drug from the systemic circulation and from bile. This toxicity is alleviated by the provision of protein as polypeptide in the elemental diet. No toxicity to the drug is seen at this dose in rats fed a regular Chow diet. If these results are applicable to humans, the use of elemental liquid diets as the only source of enteral nutrition would appear contraindicated in patients receiving methotrexate.