Kinetics of tissue distribution and elimination of retinoid drugs in the rat. II. Etretinate.

Rats were injected with single intravenous doses of etretinate (6 mg/kg), and concentrations of the drug and its metabolites, acitretin and 13-cis-acitretin, were determined in plasma and nine tissues up to 96 hr. A newly developed sensitive method for the determination by HPLC of the three retinoids in tissues was used. Etretinate rapidly appeared in most tissues and underwent a redistribution from highly perfused organs into muscle, skin, and ultimately, adipose tissue. Tissue/plasma concentration ratios ranged from 14 to 1, with the highest value in adipose tissue. In this tissue, maximum concentration was reached after 1.5 hr and remained practically constant up to 96 hr. Etretinate was rapidly hydrolyzed to form acitretin at concentrations that surpassed those of the parent drug in plasma, liver, kidney, and brain. After 6 hr, approximately 45% of etretinate had been metabolized to acitretin and approximately 40% to unidentified metabolites. These metabolites were not observed in tissues after 6 hr postdose. The parent drug was not observed 12 hr postdose, except for 6% of the dose remaining in adipose tissue. Etretinate elimination, in most tissues, was biphasic with terminal half-lives of 41 hr in skin, 1-6 hr in other lean tissues, and 1.7 hr in plasma. A volume of distribution of 1.7 liters/kg was determined, and a clearance of 12 ml.min-1.kg-1. Etretinate is characterized by rapid metabolism, transient storage in skin, and prolonged storage at a low level in adipose tissue as a deep compartment. A comparison of the pharmacokinetics of the closely related retinoids, etretinate and acitretin, disclose very pronounced differences.