Pharmacokinetic assessment of teratologically effective concentrations of an endogenous retinoic acid metabolite

Retinoic acid is a natural vitamin A derivative that undergoes oxidative metabolism in the body to yield several metabolites, which apparently represent the products of a detoxification pathway. To assess if such metabolic conversions diminished teratogenic potency, one of the major metabolites (4‐oxo‐all‐trans‐retinoic acid) was tested for its teratogenic activity in pregnant ICR mice and further investigated for its pharmacokinetic features to determine if it accumulated in the embryo in concentrations sufficient to elicit a teratogenic response. Administration of single oral doses (10, 25, 50, or 100 mg/kg) of the compound to ICR mice on day 11 of gestation. (plug day = day 0) produced dose‐dependent frequencies of serious fetal anomalies of the type usually associated with the use of retinoic acid and other retinoids. The metabolite was equivalent in teratogenic potency to retinoic acid, and, in the instance of cleft palate frequency, it was even more active. Concentrations of 4‐oxo‐all‐trans‐retinoic acid and its 13‐cis isomer were measured in the maternal plasma and whole embryos at 30 min to 10 hr after administration of the lowest (10 mg/kg) and the highest (100 mg/kg) teratogenic dose of 4‐oxo‐all‐trans‐retinoic acid by means of high‐performance liquid chromatography methodology. Distribution of the compound in the maternal system and transfer to the embryo occurred rapidly with either dose. Peak concentration in the maternal plasma and the embryo persisted for 3–4 hr after the higher dose but not with the lower dose; however, elimination kinetics for the two dose levels were similar. Irrespective of the dose, the half‐life of the compound was longer in the embryo than in the maternal plasma. The values for the area under the concentration vs. time curve in the embryo, 3.5 μg.hr/g after the lower dose and 13.6 μg.hr/g after the higher dose, provided a preliminary estimate of teratologically effective retinoid levels since the two dose levels elicited a minimal (25%) and a maximal (100%) teratogenic response, respectively. From these results we conclude that 1) 4‐oxo‐trans‐RA is a potent teratogen, 2) it may contribute substantially to the teratogenic activity of all‐trans‐RA, and 3) AUC values, as reported here, may serve as a basis for comparison of teratogenic potencies of other retinoids being developed as therapeutic agents.