Systemic pharmacokinetics of acitretin, etretinate, isotretinoin, and acetylenic retinoids in guinea pigs and obese rats

Abstract

Etretinate, a highly lipophilic retinoid, is known to accumulate in the human body with a slow systemic elimination (half-life approximately 100 days) after long-term treatment. Retinoids with high lipophilicity and slow body elimination have the propensity of eliciting teratogenic effects. Therefore, synthetic retinoids with reduced systemic retention are desired. In this study, we evaluated the systemic pharmacokinetics of acitretin, etretinate, isotretinoin, synthetic acetylenic retinoic acids (AGN 190121, AGN 190186, and AGN 190299), and acetylenic retinoates (AGN 190073, AGN 190089, and AGN 190168) in guinea pigs following iv doses. Their pharmacokinetics were also measured in obese rats to probe the effect of body fat on the drug disposition of retinoids. The acetylenic retinoates were hydrolyzed to their corresponding free acids at a much faster rate than etretinate in both animal species. All retinoates showed faster body clearance and larger volume of distribution than their free acids. In the obese rats, longer elimination half-lives and slower body clearance of the retinoids, except isotretinoin, were observed as compared to those in the normal rats. These results suggest that body fat has a significant effect on drug disposition and slows down the systemic clearance of retinoids. Since the synthetic acetylenic retinoates rapidly converted to their less lipophilic free acids after systemic absorption, the potential accumulation of these retinoids, as reported for lipophilic etretinate, were unlikely to occur in humans and animals.