ACITRETIN ELIMINATION IN SPRAGUE-DAWLEY RATS PRETREATED WITH PHENOBARBITAL OR BETA-NAPHTHOFLAVONE

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. Ani mals were killed 24 hr after dosing, and livers were removed. Hepatic microsomal protein was isolated, frozen, and later used for quantitati on 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 meta bolite isoacitretin were quantified by reversed-phase HPLC. PB pretrea tment increased the systemic clearance (CL(s)) of acitretin 33%, but d id not statistically significantly affect the volume of distribution ( V-ss) or mean residence time (MRT). PB pretreatment increased hepatic microsomal protein and total P450 concentrations, and increased the ac tivity of MROD 7-fold, EROD 8-fold, PROD 121-fold, and BROD 106-fold, BNF pretreatment increased acitretin CL(s) 152% and reduced MRT by two -thirds; V-ss was unchanged. Hepatic microsomal protein and total P450 concentrations were increased after BNF pretreatment, as were the act ivities of MROD 20-fold, EROD 32-fold, PROD 1-fold, and BROD 6-fold. T hese results indicate that PB moderately induces acitretin CL(s) in Sp rague-Bawley rats, but the magnitude of induction suggests that the pr edominant PB-inducible enzymes do not play a major role in acitretin e limination. BNF pretreatment substantially increased acitretin CL(s) i n male Sprague-Dawley rats, which strongly implicates involvement of P 4501A1 and/or 1A2, and suggests the potential for clinically relevant interactions between acitretin disposition and drugs and activities th at induce these pathways.