Etretinate accumulates in adipose tissue; this appears to account for its long terminal elimination phase in psoriatic patients. The purpose of the present study was to investigate the pharmacokinetic profile of etretinate and acitretin in a genetically obese rodent model, the Zucker rat. Pairs of obese and lean Zucker rats were dosed intravenously (0.5 mg/kg) and blood samples were collected. Plasma concentrations of etretinate and its major metabolites, acitretin and the cis isomer of acitretin (isoacitretin), were assayed by HPLC. The systemic clearance (CLs) of etretinate and the formation clearance (CLf) of the metabolite (acitretin) were lower in the obese rats (132 and 62.4 mL/min, respectively) compared with their lean littermates (197 and 126 mL/min, respectively). The remaining metabolic clearance (CLd) was identical for the lean and obese animals (70.9 and 69.9 mL/min, respectively). The ratio of metabolite-to-parent drug area under the plasma concentration-time curve (i.e., acitretin:etretinate) in the obese animal was less than that value in the lean animals (0.348 versus 0.811, respectively) following the administration of etretinate. Despite a doubling in the mean value (204 versus 87.9 mL), no statistically significant differences in the volume of distribution term for etretinate (Vdss) was observed in the obese animals, due to the large interanimal variability. The terminal phase half-life (t1/2) was significantly longer in the obese rats (3.52 versus 1.25 h). Following acitretin administration, no statistically significant differences were observed between the obese and lean animals for any of the parameters (CLs, Vdss, MRT, t1/2) of acitretin.(ABSTRACT TRUNCATED AT 250 WORDS)