All-trans-retinoic acid in maternal plasma and teratogenicity in rats and rabbits

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 and Cmax were 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.