TRANSPLACENTAL PHARMACOKINETICS OF A SYNTHETIC RETINOID WHICH IS NOT BOUND BY MOUSE EMBRYONIC CELLULAR RETINOIC ACID-BINDING PROTEIN

Teratogenicity is a major side effect of retinoids, a class of compoun ds used in dermatology and oncology. The binding of retinoids to cellu lar retinoic acid-binding protein (CRABP) has been suggested to be imp ortant for the mechanism of retinoid embryopathy, Here data are presen ted on the transplacental pharmacokinetics of CD394 (4-[3-(1-adamantyl )-4-methoxybenzamido] benzoic acid) which does not bind to murine embr yonic CRABP, although it is active in rat whole embryo culture and ter atogenic in the rabbit in vivo. A single intragastric dose of CD394 (1 0 mg/kg) was administered to mice on day 11 of gestation. The extent o f placental transfer of CD394, determined by HPLC, resembled more that of 13-cis-retinoic acid which also does not bind to CRABP, than that of the CRABP-binding all-trans-retinoic acid. C-Max values of CD394 ob tained after 1-2 h were: 1368 +/- 652 ng/ml for plasma, 203 +/- 132 ng /g for embryo and 856 +/- 563 ng/g for placenta. AUC (area-under-the-c oncentration-time-curve) values (0-12 h) were: 4319 ng x h/ml for plas ma, 751 ng x h/g for embryo and 3163 ng x h/g for placenta. Thus, CD39 4 reached the embryo, although embryonic AUC values were less than one fifth of the maternal plasma AUC values. CD394 did not alter endogeno us retinol concentrations in plasma, embryo, yolk sac or placenta. Our results indicate that CD394 reaches the embryo in vivo without bindin g to CRABP, although embryonic concentrations stayed well below plasma levels, This supports the opinion that binding to embryonic CRABP is not a prerequisite for reaching effective embryo concentrations and fo r the teratogenicity of retinoids.