The effects of folic or folinic acid on the toxicity of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3,4-dichlorobenzyloxy)-1,3,5-triazine hydrochloride, an antifolate, in dogs.

Oral doses of 5 mg/kg/day of 4,6 diamino-1,2-dihydro-2,2-dimethyl-1-(3,4-dichlorobenzyloxy)-1,3,5-triazine hydrochloride (TAD) for 28 consecutive days were tolerated by beagle dogs. Repeated doses of 15 or 42.5–45 mg/kg/day produced emesis, hemorrhagic diarrhea, anorexia, and severe weight loss, a pattern of toxicity resembling that of antifolates. Reticulocytopenia associated with erythroid depression of bone marrow, neutrophilia, and lymphopenia occurred. Histopathologic changes included atrophy, depletion and/or necrosis of the lymphoid tissue, degenerative, inflammatory, and atrophic changes of the gastrointestinal tract, and depression of the bone marrow. Simultaneous im administration of folinic acid (0.3 mg/kg/day) with TAD, but not oral folic acid (7.5 mg/kg/day), protected beagles against TAD toxicity. The demonstration of folate and antifolate toxic antagonism suggests toxic doses of TAD inhibit the reduction of folic acid to a tetrahydro derivative and thus interfere with the transfer and utilization of the single carbon moiety which is essential for a number of metabolic pathways.