Leucovorin and maximum tolerated dose toxicity of methotrexate in rats

High-does methotrexate (HD-MTX) is widely used in combination chemotherapy and can be handled without life-threatening toxicity in combination with le ucovorin (LV) rescue. However, in an experimental animal model for testing of short-term HD-MTX effects in anesthetized rats, the authors previously d emonstrated intolerable toxicity and death within a few hours in some anima ls. Serum levels were below levels routinely found in patients on HD-MTX tr eatment. This study was aimed at disclosure of possible mechanisms for acut e toxicity of MTX in rats. The previously determined maximum tolerated dose of 5 g/kg MTX was used as the test dose. The animals that died showed sudd en reduction in heart rate and blood pressure, LV, 1 g/kg infused immediate ly prior to MTX, changed MTX elimination kinetics, but did not change the a cute toxicity. The data of this study together with additional evidence obt ained in the experimental model, suggest that MTX acute toxicity may not be related to its antiproliferative effect, but rather to perturbation of end othelial cell and platelet function.