Interaction of dantrolene with the hepatic mixed function oxidase system.

Abstract

Dantrolene pretreatment of rats (100 mg/kg/day for five days) causes a fifty percent decrease in hepatic mixed function oxidase (MFO) system activity and a fifty percent decrease in cytochrome P450 content. Recovery of hepatic MFO system activity after discontinuing dantrolene therapy is slow (only sixty-three percent recovery in ten days) and greatly exceeds the half-life of dantrolene in rats (thirty-one minutes). The inactivation of the hepatic MFO system and the slow-recovery of its activity is apparently caused by dantrolene binding and forming a stable complex with hepatic proteins. 14C-dantrolene (1.0 mg/kg) administered i.v. eighteen hours before sacrificing the rats forms a stable complex with hepatic microsomal and soluble proteins. The dantrolene binding to hepatic proteins is decreased by phenobarbital pretreatment and is enhanced by diethylmaleate pretreatment.