All-Trans-Retinoic Acid in Maternal Plasma and Teratogenicity in Rats and Rabbits

Abstract

The teratogenicity of all-trans-retinoic acid, 13-cis-retinoic acid, and retinol was investigated in pregnant Wistar rats given a single oral dose on Day 10 of gestation. External malformations showed dose-dependent increases and the order of potency was all-trans-retinoic acid > retinol > 13-cis-retinoic acid. The metabolites in maternal plasma were determined following a single oral dose on Day 10 of gestation. Equipotent teratogenic doses of all-trans-retinoic acid and 13-cis-retinoic acid had similar plasma levels of all-trans-retinoic acid; however, retinol teratogenicity could not be accounted for by circulating all-trans-retinoic acid or its metabolites. The teratogenicity and maternal pharmacokinetics of all-trans-retinoic were compared in pregnant Wistar rats when given as a single dose (50 mg/kg) and as three equal doses (16.66 mg/kg) over 6 hr. Divided doses were of slightly greater potency than the single dose but the maximum observed concentration (Cmax) and area under the plasma concentration–time curve (AUC) values for the second and third doses were greatly attenuated compared with the first dose; in consequence, both the total AUC andCmaxwere reduced compared with the single dose. The altered profile could not be explained by increased formation of all-trans-retinoic acid glucuronide or increased isomerisation to 13-cis-retinoic acid. The maternal plasma levels of all-trans-retinoic acid in pregnant rabbits were reduced by a dose given 24 hr earlier. These data show that all-trans-retinoic acid in maternal plasma is a poor indicator of fetal exposure to teratogenic risk.