TERATOGENICITY AND TRANSPLACENTAL PHARMACOKINETICS OF 13-CIS-RETINOICACID IN RABBITS

No embryotoxic or teratogenic effects, considered to be treatment rela ted, were observed in rabbits after daily oral doses of 3 mg/kg of 13- cis-retinoic acid (13-cis-RA) from Day 8 to Day 11 of gestation. In co ntrast, treatment with 15 mg/kg/day significantly increased the rate o f fetal resorptions (22%) and 13 out of 68 surviving fetuses (16%) wer e malformed. Pharmacokinetic studies with both dosing regimens of 13-c is-RA in pregnant rabbits showed that on Day 11 of gestation, high con centrations of parent compound, 13-cis-RA, and its major metabolite, 1 3-cis-4-oxoRA, existed in maternal plasma. Much lower concentrations w ere found for all-trans-4-oxoRA and all-trans-RA. The area under the c oncentration-time curve (AUC) of all-trans-RA following the 15 mg/kg/d ay dosing regimen of 13-cis-RA was only 1.2% that of parent compound 1 3-cis-RA. At this dose, embryo levels of 13-cis-RA, 13-cis-4-oxoRA, an d all-trans-4-oxoRA were 2.5-, 4.7-, and 3.6-fold higher by AUC compar ison (24-hr period of Day 11) compared with the dose of 3 mg/kg. Howev er, embryo levels of all-trans-RA were virtually identical at both dos es and were, in fact, somewhat lower than endogenous concentrations me asured in untreated rabbit embryos. In contrast to mice, where isomeri zation from 13-cis- to all-trans-RA was suggested to be crucial for th e teratogenic action of 13-cis-RA, we found that the teratogenic actio n of 13-cis-RA (15 mg/kg/day) in rabbits is characterized by increased whole embryo concentrations of 13-cis-RA, 13-cis-4-oxoRA, and all-tra ns-4-oxoRA, but not of all-trans-RA. (C) 1994 Academic Press, Inc.