© 1993 Oxford University Press
research-article |
Leucovorin Protection against Repeated Daily Dose Toxicity of Trimetrexate in Rats
Department of Pathology and Experimentai Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company 2800 Plymouth Road, Ann Arbor, Michigan 48105
Received October 30, 1992; accepted April 23, 1993
Repeated high doses of trimetrexate (TMX), a potent non-classical antifolate, have been administered as an experimental treatment for life-threatening Pneumocystis carinii infections in man. This therapy includes the coadministration of leucovonn, a reduced folate cofactor, to prevent antifolate toxicity in the host. The purpose of this investigation was to assess possible toxicologic sequelae of this combination regimen in an animal model. TMX at daily oral doses of 25, 35, and 45 mg/kg produced dose-related myelosuppression, thymic lymphoid depletion, seminiferous tubular atrophy, and degenerative lesions of the gastrointestinal tract. Mortality observed with TMX alone occurred earlier at higher doses and was specifically associated with severe degenerative enteropathy of the cecum. Oral leucovorin doses of 1, 5, 20, or 50 mg/kg administered twice daily, at the time of TMX administration and 6 hr later, protected against TMX lethality and target organ toxicity in a dose-related manner. Leucovorin was only partially protective against TMX-induced macrocytic anemia and the degree of protection was not dose-related. Leucovorin protection against cecal enteropathy was associated with increased DNA synthetic rates and higher mitotic activity of cecal epithelium than those in rats administered TMX alone. Importantly, the combination of daily administration of high dose TMX for 4 weeks with protective coadministration of leucovorin did not result in target organ toxicities that differed from TMX alone.