HIGH-DOSE 7-HYDROXYMETHOTREXATE - ACUTE TOXICITY AND LETHALITY IN A RAT MODEL

To elucidate mechanisms for methotrexate (MTX)-induced renal and hepat ic toxicity, we investigated the acute effects of bolus plus continuou s infusion of up to 0.4 g/kg 7-hydroxymethotrexate (7-OH-MTX) in the r at. We demonstrate for the first time in any species the occurrence of acute lethal toxicity within a few hours after 7-OH-MTX administratio n. Serum concentrations of 7-OH-MTX measured at the time of death were 1.4 mM (mean), about one-half of those achieved in some patients afte r infusion of high-dose MTX (HD-MTX) in the clinic. The data suggest a n approximate LD(50) (the dose lethal to 50% of the study population) of 0.3 g/kg and a steep dose/lethality curve for 7-OH-MTX. Moreover, a cute renal and hepatic toxicity occurred as evidenced by severe morpho logical findings and increased serum levels of creatinine and liver tr ansaminases. In all rats subjected to continuous infusion of 7-OH-MTX, yellow microscopic precipitations were apparent in the kidney tubules . Crystallization was also seen in bile ducts of the liver in some of the rats. These results further support that the formation of 7-OH-MTX is disadvantageous and that reported attempts to prevent its formatio n during MTX treatment are warranted.