Selective agonists of retinoic acid receptors: Comparative toxicokinetics and embryonic exposure
Three biologically active synthetic retinoids were investigated that bind selectively to retinoic acid receptors RARs (α, β and γ). The retinoids were previously demonstrated to have different teratogenic effects in the mouse in terms of potency and regioselectivity. The teratogenic potency rank order (α > β > γ) was found to be more or less compatible with the receptor binding affinities and transactivation potencies of the retinoid ligands to their respective receptors. The RARα agonist (Am580; CD336) induced a wide spectrum of malformations: CD2019 (RARβ agonist) and especially CD437 (RARγ agonist) produced more restricted defects. In the current study we tried to address whether the differences in teratogenic effects are solely related to binding affinity and transactivation differences or also due to differences in embryonic exposure. Therefore, transplacental kinetics of the ligands were assessed following administration of a single oral dose of 15 mg/kg of either retinoid given to NMRI mice on day 11 of gestation. Am580 was rapidly transferred to the embryo resulting in the highest embryonic exposure [embryo to maternal plasma area under the time vs concentration curve (AUC)(0-24h) ratio (E/M) was 1.7], in accordance 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 teratogenic, exhibited considerable embryonic exposure (E/M of 0.6). These findings suggest that both the embryonic exposure and receptor binding transactivation selectivity are crucial determinants of the teratogenicity of these retinoid ligands.
Arafa, Husam M.M.; Elmazar, Mohamed M.; Hamada, Farid M.A.; Reichert, Uwe; Shroot, Braham; and Nau, Heinz, "Selective agonists of retinoic acid receptors: Comparative toxicokinetics and embryonic exposure" (2000). Pharmacy. 224.