Stereoselective distribution of the teratogenic thalidomide analogue EM12 in the early embryo of marmoset monkey, Wistar rat and NMRI mouse

Abstract

Thalidomide administration during early gestation results in specific and dramatic limb defects in primates, but not in laboratory rodents such as the rat and mouse. The thalidomide analogue EM12 [2-(2,6-dioxopiperidine-3-yl)-phthalimidine] was used in the present study because this compound is metabolically more stable and teratogenically more potent than thalidomide in the monkey. We have administered the pure enantiomers, since we have previously shown that S-EM12 proved to be much more teratogenic in the monkey than R-EM12. In maternal plasma, placenta and embryo of the pregnant marmoset monkey (Callithrix jacchus) and Wistar rat, the concentrations were investigated of the enantiomers and their metabolites after administration of R- and S-EM12. With whole body autoradiography the distribution in the embryo, including the target tissue, the embryonic limb bud was examined in the NMRI mouse and marmoset monkey. Our investigations showed that both the R- and the S-enantiomers were transferred to the embryo during organogenesis [monkey, gestation day (GD) 61; rat, GD 12; mouse, GD 10]. The gestation period chosen was toward the end of the thalidomide-sensitive stage, but yielded sufficient gestational material for analysis. Considerable amounts of the enantiomers were produced via racemization of the administered pure enantiomers and were present in maternal plasma as well as in placenta and embryo. In the monkey, the racemization were stereoselective: the S-enantiomer was eliminated more slowly in the monkey than the R-enantiomer, possibly because of stereospecific binding and metabolism. In the plasma and embryo of both rat and monkey, the metabolites were detected in considerably lower concentrations than EM12, emphasizing the importance of the parent drug in regard to the teratogenic effect. The whole-body autoradiography in marmoset and mouse showed high radioactivity in the embryonic CNS, the branchial apparatus and in the limb buds. The S-enantiomer of EM12 was more strongly concentrated than the R-enantiomer in these areas. In the limb buds, the highest concentrations of radioactivity were observed in the periphery, sometimes 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 must demonstrate if this accumulation has implications for the mechanism of thalidomide teratogenesis in primate species.

The effect of thalidomide in chicken embryos

“…We were also interested to determine whether the thalidomide enantiomers (R and S) and those of its more potent analog EM12 differ in their effects on explanted limb buds as they do in monkey embryos (Merker et al, 1988;Heger et al, 1994;Schmahl et al, 1996). Our data show that whereas R-thalidomide and R-EM12 do cause some limb defects, the S version of each is considerably more potent (Fig.…”

Thalidomide Modulates Nuclear Redox Status and Preferentially Depletes Glutathione in Rabbit Limb versus Rat Limb

“…Although specific reasons for increased ROS production in rabbits are unknown, thalidomide pharmacokinetics between sensitive and insensitive species demonstrates differences in embryonic regions of accumulation. Schmahl et al (1996) showed that in utero exposure to radioactively labeled EM12, a highly teratogenic thalidomide derivative, to thalidomide-sensitive marmosets resulted in the preferential accumulation in the limb of, compared with other embryonic regions. Moreover, preferential accumulation of EM12 in the limb was not evident in thalidomide-resistant species, the rat and mouse (Schmahl et al, 1996).…”

“…Schmahl et al (1996) showed that in utero exposure to radioactively labeled EM12, a highly teratogenic thalidomide derivative, to thalidomide-sensitive marmosets resulted in the preferential accumulation in the limb of, compared with other embryonic regions. Moreover, preferential accumulation of EM12 in the limb was not evident in thalidomide-resistant species, the rat and mouse (Schmahl et al, 1996). Specific pharmacokinetics of thalidomide in rat and rabbit embryos have not been identified as of yet, but may account for the increased susceptibility to thalidomideinduced oxidative stress in the rabbit LBC.…”

Investigation of the stereodynamics of molecules and catalyzed reactions by CE

“…Racemic thalidomide (Contergan s , 2-(2,6-dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione) was introduced in 1956 as a sedative and antinausea drug especially in the first trimester of pregnancy. (S)-(À)-thalidomide has proven to have severe teratogenic effects in animal experiments [81]. Infants born to women who used thalidomide had a high incidence of deformities in their limbs [82].…”