Failure of phenobarbital or butanediol pretreatment to potentiate tienilic acid hepatotoxicity in vivo in the rat.

Tienilic acid, a uricosuric diuretic, has been associated with hepatocellular injury in humans as a low-incidence adverse reaction. This phenomenon suggests that a metabolic idiosyncrasy may be involved. In the present study, the effect of phenobarbital and 1,3-butanediol pretreatment, prior to tienilic acid challenge (50 or 100 mg/kg, i.v.) on rat hepatic function was studied in vivo. The following parameters were assessed: plasma alanine amino-transferase activity, plasma bilirubin concentration and bile flow. The results show that neither pretreatment would reveal that tienilic acid possesses hepatotoxic properties in the rat. The discrepancies between these results observed in vivo and those obtained by others in the isolated perfused rat liver suggest: a) that a metabolite formed (under normal conditions) via the phenobarbital- or butanediol-inducible forms of cytochrome P-450 is not a likely part of the hepatotoxic sequence of events; b) that the isolated perfused rat liver model in this case is not representative of the in vivo situation.