Abstract

Male Sprague-Dawley rats were pretreated with either phenobarbital (PB) or beta-naphthoflavone (BNF), after which acitretin (0.84-0.86 mg/kg) was administered intravenously and plasma was sampled with time. Animals were killed 24 hr after dosing, and livers were removed. Hepatic microsomal protein was isolated, frozen, and later used for quantitation of hepatic microsomal protein concentration, total cytochrome P450 concentration, and microsomal activities of methoxy-, ethoxy-, pentoxy-, and benzyloxyresorufin O-dealkylation (MROD, EROD, PROD, and BROD, respectively). Plasma concentrations of acitretin and its primary metabolite isoacitretin were quantified by reversed-phase HPLC. PB pretreatment increased the systemic clearance (CLs) of acitretin 33%, but did not statistically significantly affect the volume of distribution (Vss) or mean residence time (MRT). PB pretreatment increased hepatic microsomal protein and total P450 concentrations, and increased the activity of MROD 7-fold, EROD 8-fold, PROD 121-fold, and BROD 106-fold. BNF pretreatment increased acitretin CLs 152% and reduced MRT by two-thirds; Vss was unchanged. Hepatic microsomal protein and total P450 concentrations were increased after BNF pretreatment, as were the activities of MROD 20-fold, EROD 32-fold, PROD 1-fold, and BROD 6-fold. These results indicate that PB moderately induces acitretin CLs in Sprague-Dawley rats, but the magnitude of induction suggests that the predominant PB-inducible enzymes do not play a major role in acitretin elimination. BNF pretreatment substantially increased acitretin CLs in male Sprague-Dawley rats, which strongly implicates involvement of P4501A1 and/or 1A2, and suggests the potential for clinically relevant interactions between acitretin disposition and drugs and activities that induce these pathways.