Transplacental pharmacokinetics of teratogenic doses of etretinate and other aromatic retinoids in mice.
The transplacental pharmacokinetics of single teratogenic doses of etretinate and motretinide were compared with particular emphasis on distribution and concentrations in the exposed embryos of the free acid metabolite, etretin. The three aromatic retinoids were also tested for their direct inhibitory effect on chondrogenesis in the limb bud mesenchymal cell "micromass" culture assay. After a standard dose of 100 mg/kg administered on day 11 of gestation in NMRI mice, all three compounds were teratogenic, but they differed from each other in potency. Etretinate was most active as a teratogen, equalling the potency of our standard all-trans-retinoic acid; every exposed fetus was deformed with severe shortening of all limb bones as well as cleft palate. Etretin was less potent than etretinate, and motretinide was considerably less active as a teratogen than the other two. In the in vitro assay, only etretin suppressed chondrogenesis and this activity was equivalent to that of all-trans-retinoic acid (IC50 of 12 ng/ml). Both etretinate and motretinide (which contain an ethyl ester and ethylamide terminal group, respectively) were essentially inactive in vitro, demonstrating the fact that a free carboxylic group may be a requirement for the in vitro suppression of chondrogenesis. These differences between the results obtained in vivo and in vitro could be resolved by pharmacokinetic investigations using HPLC methods. Both etretinate and motretinide were metabolized in vivo to etretin, their likely common teratogenic metabolite. The high teratogenic potency of etretinate was probably the result of high concentrations as well as AUC values of its metabolite etretin in the embryo. On the other hand, the comparatively low teratogenicity of motretinide could be related to approximately 5 x lower embryonic peak levels as well as AUC values of etretin. A comparison of these results with those previously obtained for all-trans- and 13-cis-retinoic acids confirms the correlation between embryonic exposure and teratogenic potency in the mouse. Our results indicate that pharmacokinetic studies are essential for the interpretation of relative teratogenic potencies of retinoids as well as apparent differences between in vivo and in vitro teratogenesis. A free carboxyl group at the terminal end of the tetraene chain was necessary for high activity of the retinoids studied.
Reiners
J
J
Institute of Toxicology and Embryopharmacology, Free University Berlin, F.R.G.
Löfberg
B
B
Kraft
J C
JC
Kochhar
D M
DM
Nau
H
H
D000014:Abnormalities, Drug-Induced / Q000196:embryology*; D017255:Acitretin; D000818:Animals; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D005050:Etretinate / Q000493:pharmacokinetics*; D005260:Female; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D014212:Tretinoin; D005050:Etretinate; D017255:Acitretin; C010832:motretinide