Pharmacokinetic profile of two aromatic retinoids (etretinate and acitretin) in the obese Zucker rat.

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)

[1]  D. Abernethy,et al.  Pharmacokinetics and dynamics of (+/-)-verapamil in lean and obese Zucker rats. , 1986, The Journal of pharmacology and experimental therapeutics.

[2]  D. Greenblatt,et al.  Drug Disposition in Obese Humans , 1986, Clinical pharmacokinetics.

[3]  P. McNamara,et al.  Renal function in the obese Zucker rat. , 1986, International journal of obesity.

[4]  W. Colburn,et al.  Etretinate kinetics during chronic dosing in severe psoriasis , 1985, Clinical pharmacology and therapeutics.

[5]  P. McNamara,et al.  Phenobarbital in the genetically obese Zucker rat. I. Pharmacokinetics after acute and chronic administration. , 1984, The Journal of pharmacology and experimental therapeutics.

[6]  P. McNamara,et al.  Phenobarbital in the genetically obese Zucker rat. II. In vivo and in vitro assessments of microsomal enzyme induction. , 1984, The Journal of pharmacology and experimental therapeutics.

[7]  E. Farber,et al.  Psoriasis. A review of recent advances in treatment. , 1984, Drugs.

[8]  J. Geiger,et al.  Clinical evaluation of an aromatic retinoid, RO 10-1670, in severe psoriasis , 1984 .

[9]  A. Vahlquist,et al.  Retinoid concentrations in skin, serum and adipose tissue of patients treated with etretinate * , 1983, The British journal of dermatology.

[10]  W. Colburn,et al.  Pharmacokinetics of the retinoids isotretinoin and etretinate. A comparative review. , 1982, Journal of the American Academy of Dermatology.

[11]  D. Greenblatt,et al.  Pharmacokinetics of Drugs in Obesity , 1982, Clinical pharmacokinetics.

[12]  K. Stöckel,et al.  ON METABOLISM AND PHARMACOKINETICS OF AN AROMATIC RETINOID , 1981, Annals of the New York Academy of Sciences.

[13]  L. Zucker.  HEREDITARY OBESITY IN THE RAT ASSOCIATED WITH HYPERLIPEMIA * , 1965, Annals of the New York Academy of Sciences.