Hepatic Enzyme Induction Potential of Acitretin in Male and Female Sprague–Dawley Rats

Abstract Certain retinoids have been shown in rats and mice to induce the hepatic cytochrome P‐450 enzyme system, and evidence from our laboratory suggested that acitretin, the active primary metabolite of etretinate (a retinoid used in the treatment of psoriasis) may induce its own metabolism. To test this hypothesis, male and female Sprague–Dawley rats were orally pretreated with acitretin for 18 days (10 mg/kg/day) and intravenously dosed with acitretin on day 20 (0.8–0.9 mg/kg). Serial blood samples were taken through 24 h, after which the hepatic microsomal proteins were harvested. Plasma concentrations of acitretin and its main metabolite isoacitretin were determined by HPLC, and total hepatic cytochrome P‐450 concentratons and activities were determined using standard methods. Systemic clearance (17.4 ± 2.5 and 12.1 ± 1.6 mL/min per kg in control males and females, respectively), volume of distribution at steady state ( V ss  = 1568 ± 353 and 1589 ± 488 mL in control males and females, respectively), and mean residence time (MRT = 1.50 ± 0.23 and 2.22 ± 0.70 h in control males and females, respectively) were unchanged by acitretin pretreatment. Systemic clearance was 44% higher in control males than females. Concentrations of total microsomal protein (13.8 ± 1.6 and 8.4 ± 1.2 mg/g of liver in control males and females, respectively) and total P‐450 (0.433 ± 0.041 and 0.425 ± 0.104 nmol/mg microsomal protein in control males and females, respectively) were also unchanged by acitretin pretreatment, as were microsomal levels of methoxy‐, ethoxy‐, pentoxy‐, and (benzyloxy)resorufin O‐dealkylation (MROD, EROD, PROD, and BROD, respectively) (control males and females, respectively, expressed as pmol of resorufin formed/min per mg of microsomal protein: MROD = 37.7 ± 4.5 and 30.6 ± 4.2; EROD 276 ± 40 and 208 ± 59; PROD = 15.2 ± 4.5 and 5.8 ± 1.2; and BROD 93.7 ± 24.4 and 15.5 ± 3.9). The results indicate that acitretin clearance was higher in males than females, and that acitretin given orally to Sprague–Dawley rats at a dosage of 10 mg/kg/day for 18 days did not induce its own metabolism and did not alter the hepatic concentration of total P‐450 nor its activities for MROD, EROD, PROD, or BROD.