Influence of pregnancy on the pharmacokinetic disposition of two aromatic retinoids (etretinate and acitretin) in the rat. I. Intravenous studies

Abstract

The influence of pregnancy on the disposition of two related aromatic retinoids (etretinate and its metabolite, acitretin) was evaluated in a rodent model. The plasma concentrations of etretinate and acitretin were monitored by a specific HPLC method following iv bolus doses to 17-day pregnant and nonpregnant Sprague-Dawley rats. The systemic clearance of etretinate was significantly lower in the pregnant rats compared to nonpregnant controls (129 vs. 185 ml/hr, respectively; p less than 0.05). This decrease was entirely due to a lower formation clearance of acitretin (acid) from etretinate (ester) in the pregnant animals (96 vs. 146 ml/hr; p less than 0.05). The in vitro plasma hydrolysis rate of etretinate was also lower in the pregnant animals. By contrast, the systemic clearance of acitretin was greater in the pregnant compared to the nonpregnant control animals (184 vs. 145 ml/hr, respectively; p less than 0.05). The apparent volumes of distribution for both retinoids were comparable in the pregnant and nonpregnant animals. Etretinate infusions in nonpregnant animals yielded systemic clearances (mean = 164 ml/hr) which were similar to those obtained for bolus dose experiments. Acitretin clearance increased (plasma levels decreased) following acitretin infusion to nonpregnant rats over the time course of the infusion. The results illustrate the marked effect of pregnancy on the disposition of these retinoids and suggest that acitretin may pose less of a teratogenic hazard than the parent compound etretinate.