KINETICS OF TISSUE DISTRIBUTION AND ELIMINATION OF RETINOID DRUGS IN THE RAT .2. ETRETINATE

Rats were injected with single intravenous doses of etretinate (6 mg/k g), 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 o f the three retinoids in tissues was used. Etretinate rapidly appeared in most tissues and underwent a redistribution from highly perfused o rgans into muscle, skin, and, ultimately, adipose tissue. Tissue/plasm a concentration ratios ranged from 14 to 1, with the highest value in adipose tissue. In this tissue, maximum concentration was reached afte r 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, similar to 45% of etretinate had been metabolized to acitretin an d similar to 40% to unidentified metabolites. These metabolites were n ot observed in tissues after 6 hr postdose. The parent drug was not ob served 12 hr postdose, except for 6% of the dose remaining in adipose tissue. Etretinate elimination, in most tissues, was biphasic with ter minal 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 determi ned, end a clearance of 12 ml min(-1) kg(-1). Etretinate is characteri zed by rapid metabolism, transient storage in skin, and prolonged stor age at a low level in adipose tissue as a deep compartment. A comparis on of the pharmacokinetics of the closely related retinoids, etretinat e and acitretin, disclose very pronounced differences.