Selective agonists of retinoic acid receptors: comparative toxicokinetics and embryonic exposure

Three biologically active synthetic retinoids were investigated that bind s electively to retinoic acid receptors RARs (alpha, beta and gamma). The ret inoids were previously demonstrated to have different teratogenic effects i n the mouse in terms of potency and regioselectivity. The teratogenic poten cy rank order (alpha > beta > gamma) was found to be more or less compatibl e with the receptor binding affinities and transactivation potencies of the retinoid ligands to their respective receptors, The RAR alpha agonist (Am5 80; CD336) induced a wide spectrum of malformations; CD2019 (RAR beta agoni st) and especially CD437 (RAR gamma agonist) produced more restricted defec ts. In the current study we tried to address whether the differences in ter atogenic effects are solely related to binding affinity and transactivation differences or also due to differences in embryonic exposure. Therefore, t ransplacental kinetics of the ligands were assessed following administratio n of a single oral dose of 15 mg/kg of either retinoid given to NMRI mice o n day 11 of gestation. Am580 was rapidly transferred to the embryo resultin g in the highest embryonic exposure [embryo to maternal plasma area under t he time vs concentration curve (AUC)(0) (24) (h) ratio (E/M) was 1.7], in a ccordance with its highest teratogenic potency. The low placental transfer of CD2019 (E/M of 0.3) was compatible with its lower teratogenic potential. Of major interest was the finding that the CD437, though being least terat ogenic, exhibited considerable embryonic exposure (E/M of 0.6). These findi ngs suggest that both the embryonic exposure and receptor binding transacti vation selectivity ape crucial determinants of the teratogenicity of these retinoid ligands.