HEPATIC ENZYME-INDUCTION POTENTIAL OF ACITRETIN IN MALE AND FEMALE SPRAGUE-DAWLEY RATS

Certain retinoids have been shown in rats and mice to induce the hepat ic cytochrome P-450 enzyme system, and evidence from our laboratory su ggested that acitretin, the active primary metabolite of etretinate (a retinoid used in the treatment of psoriasis) may induce its own metab olism. To test this hypothesis, male and female Sprague-Dawley rats we re orally pretreated with acitretin for 18 days(10 mg/kg/day) and intr avenously 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 p roteins were harvested. Plasma concentrations of acitretin and its mai n metabolite isoacitretin were determined by HPLC, and total hepatic c ytochrome P-450 concentrations and activities were determined using st andard methods. Systemic clearance (17.4 +/- 2.5 and 12.1 +/- 1.6 mL/m in per kg in control males and females, respectively), volume of distr ibution at steady state V-ss = 1568 +/- 353 and 1589 +/- 488 mL in con trol males and females, respectively), and mean residence time (MRT = 1.50 +/- 0.23 and 2.22 +/- 0.70 h in control males and females, respec tively) were unchanged by acitretin pretreatment. Systemic clearance w as 44% higher in control males than females. Concentrations of total m icrosomal protein (13.8 +/- 1.6 and 8.4 +/- 1.2 mg/g of liver in contr ol males and females, respectively) and total P-450 (0.433 +/- 0.041 a nd 0.425 +/- 0.104 nmol/mg microsomal protein in control males and fem ales, 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) (c ontrol 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 indicat e 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 th e hepatic concentration of total P-450 nor its activities for MROD, ER OD, PROD, or BROD.