Development of resistance to hepatotoxic effect of furylfuramide by pretreatment with its subnecrotic doses and carbon tetrachloride.

Hepatotoxicity caused by furylfuramide in ddYS male mice was further investigated with following results. (1) Pretreatment with successive oral administration of non-toxic (non-necrotizing) dose (100 mg/day) of furylfuramide for 8 or 24 days alleviated the liver damage elicited by a necrotizing dose (250 mg/kg). The pretreatment resulted in the significant enhancement of the activity of aniline hydroxylase in the liver microsome, which was reduced markedly by a single administration of 250 mg/kg (without pretreatment). The result suggests that the acquired resistance to a toxic dose of furylfuramide is due to the acceleration of detoxication of the drug. (2) Simultaneous administration of CCl4, another hepatotoxic substance, with furylfuramide reduced the lethal effect of the latter. The LD50 values of furylfuramide were increased more than 2.4 times as compared with that of furylfuramide alone. Pretreatment with a small amount of CCl4 as short period as half an hour is more effective than simultaneous administration of both substances. This inhibitory effect of CCl4 on furylfuramide may be explained by an inhibition of the metabolic activation of the latter by the former.