Effect of enzyme induction and inhibition on the fate of metronidazole and tinidazole in the rat.

The excretion routes of intact metronidazole and tinidazole were studied in rats kept in metabolism cages and cannulated for continuous bile collection. The nitroimidazoles were given intraarterially either alone or after a 5-day pretreatment with phenobarbitone (70 mg/kg/day intravenously) or after a single dose of cimetidine (50 mg/kg intraarterially). After 30 mg/kg, 27.0% of the metronidazole dose was excreted intact in 24-hr urine and 2.2% in bile. After tinidazole, the recoveries of the intact drug in urine and bile were 48.1% and 1.7%, respectively. After 90 mg/kg, the total recoveries of both drugs were 25-28% smaller than after 30 mg/kg. Phenobarbitone pretreatment did not affect metronidazole levels in plasma but decreased tinidazole levels at 4 hrs. The 24-hr recoveries of the intact nitroimidazoles in urine were significantly reduced by phenobarbitone while the 24-hr bile recoveries were not. Cimetidine treatment enhanced both metronidazole (at 1, 2 and 3 hrs) and tinidazole (only at 1 hr) concentrations in plasma, but this shift was not reflected in the 24-hr urine recoveries of the intact nitroimidazoles. Cimetidine doubled, however, the 24-hr bile recovery of the intact tinidazole. The calculations of the apparent degree of metabolism, assuming no methodological losses, showed that phenobarbitone increased the metabolism of tinidazole by about 62% and that of metronidazole only by about 16%. The effect of a single dose of cimetidine was negligible.