Isoniazid potentiation of a guinea pig model of halothane‐associated hepatotoxicity

Abstract

Isoniazid (INH) is a selective inducer of cytochrome P-450 isozymes that are involved in the biotransformation of organohalogen anesthetics. It has been used to produce a rat model of halothane-associated hepatotoxicity that was linked to enhanced oxidative biotransformation of the anesthetic. Guinea pigs were pretreated with INH in order to potentiate halothane-induced hepatic necrosis and to study the oxidative pathway as a hepatotoxic mechanism in this species. The animals received either 12.5, 25.0 or 50.0 mg kg-1 INH i.p. for 7 days. Following halothane exposure, there were dose-dependent increases in plasma levels of the oxidative halothane metabolite, trifluoroacetic acid. These increases were associated with increases in 48 h plasma alanine aminotransferase (ALT) levels. When combined with halothane exposure, the two higher doses of INH killed the animals before planned termination. These deaths were not attributable to hepatic failure. Dividing the 25 mg kg-1 INH dose into twice daily injections of 12.5 mg kg-1 reduced deaths. INH pretreatment control animals exhibited occasional non-dose-dependent increases in ALT as well as the occurrence of fatty vacuolization of hepatocytes at the highest dose. Even though INH pretreatment enhanced oxidative halothane biotransformation and subsequent hepatotoxicity, sensitivity of guinea pigs to the deleterious actions of INH would contraindicate its use as a cytochrome P-450 induction agent.