The pharmacokinetics and disposition of etretinate (ET) and its metabolites, etretin (ETA) and isoetretin (c-ETA), were studied in the dog. Administration of ET, ETA, and c-ETA by several routes of administration allowed the use of a physiologically based model to assess the relative contributions of absorption and presystemic metabolism to the oral bioavailability of these compounds. The large Vd(ss) (214 ± 228 liters/kg) of ET and terminal half-life of greater than 300 hr indicated the wide distribution and prolonged storage of ET in the tissues. After a dose of ET, its two metabolites, ETA and c-ETA, were also detectable in the plasma. The oral bioavailability of ET in the dog was 52.5% with 95.4% of the dose available for absorption from the gut lumen. Of the ET that was absorbed from the gut lumen, 26.4% and 25.5% was removed by the gut wall and liver, respectively. ETA was found to be a formation rate-limited metabolite of ET. Although the oral bioavailability of ETA could not be determined because of its administration was not possible by the iv route, it appeared that only 16% of an orally administered dose entered the portal circulation from the gut. c-ETA was detected after administration of either ET or ETA. ETA and c-ETA were shown to be interconvertible metabolites, but the equilibrium of the conversion between c-ETA and ETA favored the formation of ETA. The oral bioavailability of c-ETA was 42.4%, but the liver showed little metabolic activity toward c-ETA. The loss in bioavailability of c-ETA was almost entirely due to lack of absorption from the gut lumen and to metabolism in the gut wall.
|Number of pages
|Drug Metabolism and Disposition
|Published - Jan 1 1989