Systemic pharmacokinetics of acetylenic retinoids in rats

In order to widen the therapeutic index of retinoids, one approach is to synthesize retinoids with reduced systemic distribution. Sixteen acetylenic retinoids were evaluated for their systemic disposition kinetics in rats after iv doses. Four pharmacokinetic parameters (i.e., total body clearance, volume of distribution at steady state, mean residence time, and the elimination half-life) were calculated for all retinoids tested. These compounds were categorized into four groups according to their functional head group. Retinoic acids having the trimethylcyclohexenyl head group as isotretinoin most mimicked isotretinoin in disposition profiles among all retinoic acids examined. They had volumes of distribution similar to and mean residence times shorter than those of isotretinoin. Retinoic acids containing the tetramethyltetralinyl head group as arotinoid had extensive tissue distribution and small body clearance. They had extended elimination half-lives similar to those observed for etretinate. Dimethylchromanyl and dimethylthiochromanyl retinoic acids were more polar; their terminal half-lives were reasonably short and no extensive tissue distribution was noted. The ethyl retinoates rapidly converted to their corresponding retinoic acids after iv doses. All ethyl esters had limited systemic residence times. The ethyl nicotinates tended to have much larger body clearance (10- to 25-fold) than the ethyl benzoates. After iv administration of ethyl retinoates, the ethyl esters disappeared rapidly, while their corresponding retinoic acids became the major drug-derived species in blood. The study results demonstrated different pharmacokinetic behaviors of acetylenic retinoids with different functional head groups.