title: 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 concentrations 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 (Vss = 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).(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Division of Pharmacology and Experimental Therapeutics, College of Pharmacy, University of Kentucky, Lexington 40536-0082.
authors.forename: D S
authors.initials: DS
authors.lastname: Small
authors.forename: P J
authors.initials: PJ
authors.lastname: McNamara
mesh_terms: D017255:Acitretin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011506:Proteins; D003577:Cytochrome P-450 Enzyme System; D017255:Acitretin