EFFECTS OF CERTAIN AGENTS ON IATROGENIC HEPATOTOXICITY IN EXPERIMENTAL ANIMALS

Abstract

In the present study, the hepatotoxic effects of four drugs in current medical use, namely paracetamol, phenobarbitone, isoniazid, and rifampicin, were investigated in experimental rats. Three successful submaximal hepatotoxicity models were constructed, based on the doses reported in the literature as well as on pilot experimental trials. These are paracetamol, paracetamol-phenobarbitone, and isoniazid-rifampicin hepatotoxicity models.

For setting of the first model, paracetamol was administered in single intraperitoneal doses of 500-700 mg!kg to adult fasted and fed rats, and in single oral doses of 400-1000 mg!kg to adult fasted rats. Oral doses of 600 and 800 .mg!kg, administered to fasted adult rats, were selected as submaximal hepatotoxic paracetamol doses.

In the second model, phenobarbitone was co-administered with paracetamol to adult rats. Phenobarbitone was administered via the intraperitoneal route, in a dose of 75 mg!kg/day for three consecutive days, followed by a single oral dose of paracetamol, 600 mglkg, on fourth day.

For setting of the third model, isoniazid . and rifampicin were individually administered to young rats via the intraperitoneal route, each in a dose of 50 mg/kg/day for 21 days, and co-administered in intraperitoneal doses of 50 and I 00 mg/kg/day of each drug for 21 days. Isoniazid-rifampicin co­ administration to young rats (each in a dose of 50 mg/kg/day, i.p., 21 days) was selected to represent submaximal hepatotoxicity.

Adult rats were fasted 18 hours before paracetamol administration and remained fasted for 24 hours after paracetamol administration then sacrificed. Young rats were deprived of food 12 hours after the last drug administration, • remained fasted for 12 hours, then sacrificed. In all models, animals were

sacrificed 24 h.ours after the last hepatotoxic dose administration.