Alteration of methotrexate metabolism in rats by administration of an elemental liquid diet. II. Reduced toxicity and improved survival using cholestyramine.
The administration of an elemental, chemically defined liquid diet to rats significantly enhanced gastrointestinal toxicity associated with methotrexate administration compared with rats fed a regular chow diet. Chemotherapy induced enteritis is potentially enhanced by the abrasive effect of bile acids on the susceptible cells of the small bowel mucosa. This study evaluated the interactions of methotrexate and cholestyramine in vitro. An additional goal was to evaluate the effects of cholestyramine on animal survival and drug pharmacokinetics in rats given an elemental, chemically defined liquid diet. In vitro binding of cholestyramine to methotrexate increased in a linear fashion at varying concentrations of both drugs in phosphate buffer solution (r greater than 0.84, P less than 0.001) and in bile which was not influenced by pH (range 5-8). The addition of cholestyramine to an elemental liquid diet significantly improved survival following methotrexate administration (20 mg/kg IP bolus) compared with rats fed an elemental liquid diet alone (P less than 0.02). Both elemental liquid diets, either with or without cholestyramine, delayed serum and biliary clearance of methotrexate up to 72 hours compared with rats fed a regular chow diet. However, rats fed an elemental liquid diet with added cholestyramine had significantly lower levels of methotrexate in serum from the systemic and portal venous circulation at 48 hours (P less than 0.03) and in bile at 48 (P less than 0.02) and 72 hours (P less than 0.05) following methotrexate administration. The addition of cholestyramine to an elemental liquid diet improves survival and reduces gastrointestinal toxicity following methotrexate administration, by binding methotrexate in bile and reducing the delay in systemic clearance of the drug. By binding to intraluminal bile acids, cholestyramine may also have a locally protective effect on the mucosal cells of the small intestine following methotrexate administration. Cholestyramine may be of clinical benefit in patients receiving high-dose methotrexate regimens as an adjunct to leucovorin rescue.
D000818:Animals; D001646:Bile / Q000378:metabolism; D002792:Cholestyramine Resin / Q000008:administration & dosage*; D004032:Diet; D004347:Drug Interactions; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D051381:Rats
D002792:Cholestyramine Resin; D008727:Methotrexate