STEREOSELECTIVE DISTRIBUTION OF THE TERATOGENIC THALIDOMIDE ANALOG EM12 IN THE EARLY EMBRYO OF MARMOSET MONKEY, WISTAR RAT AND NMRI MOUSE

Thalidomide administration during early gestation results in specific and dramatic limb defects in primates, but not in laboratory rodents s uch as the rat and mouse. The thalidomide analogue EM12 [2-(2, 6-dioxo piperidine-3-yl)-phthalimidine] was used in the present study because this compound is metabolically more stable and teratogenically more po tent than thalidomide in the monkey. We have administered the pure ena ntiomers, since we have previously shown that S-EM12 proved to be much more teratogenic in the monkey than R-EM12. In maternal plasma, place nta and embryo of the pregnant marmoset monkey (Callithrix jacchus) an d Wistar rat, the concentrations were investigated of the enantiomers and their metabolites after administration of R- and S-EM12. With whol e body autoradiography the distribution in the embryo, including the t arget tissue, the embryonic limb bud was examined in the NMRI mouse an d marmoset monkey. Our investigations showed that both the R- and the S-enantiomers were transferred to the embryo during organogenesis [mon key, gestation day (GD) 61; rat, GD 12; mouse, GD 10]. The gestation p eriod chosen was toward the end of the thalidomide-sensitive stage, bu t yielded sufficient gestational material for analysis. Considerable a mounts of the enantiomers were produced via racemization of the admini stered pure enantiomers and were present in maternal plasma as well as in placenta and embryo. In the monkey, the racemization were stereose lective: the S-enantiomer was eliminated more slowly in the monkey tha n the R-enantiomer, possibly because of stereospecific binding and met abolism. In the plasma and embryo of both rat and monkey, the metaboli tes were detected in considerably lower concentrations than EM12, emph asizing the importance of the parent drug in regard to the teratogenic effect. The whole-body autoradiography in marmoset and mouse showed h igh radioactivity in the embryonic CNS, the branchial apparatus and in the limb buds. The S-enantiomer of EM12 was more strongly concentrate d than the R-enantiomer in these areas. In the limb buds, the highest concentrations of radioactivity were observed in the periphery, someti mes at the very tip of the buds. Accumulation of radioactivity in limb buds and neural epithelium relative to other areas of the embryo was much more pronounced in the monkey than in the mouse. Future studies m ust demonstrate if this accumulation has implications for the mechanis m of thalidomide teratogenesis in primate species.