Question

Table 1. Teratogenicity of the Optical Isomers of Thalidomide in New Zealand White Rabbits (based on Fabro, Shill, Normal Fetuses Malformed Fetuses Optical form administered (150 mg#Rabbits drug/kg body weight) None 5 39 0 RS 6 25 10 R(+) 7 46 8 S(-) 8 56 9 These results were disputed by Kohler, et al. (5) in 1979. They claimed that the S-enantiomer was responsible for a 47% rate of malformation of fetuses in mice and a 92% malformation in rats. They did not observe the same results with the R- enantiomer and concluded that the R-enantiomer was inactive as a teratogen. However, the validity of this study has been called into question by Scott, et al. (6) who pointed out that rats and mice are not as susceptible to the teratogenic effects of thalidomide as are New Zealand rabbits and humans. If one enantiomer is toxic, an important pharmacokinetic consideration is racemization of the two enantiomers during metabolism. This was addressed by Eriksson, et al. (7) who developed a stereoselective HPLC assay to measure the concentrations of the R- and S- enantiomers of thalidomide in blood. Adult male volunteers were given the R- or S- enantiomer or a racemic mixture of thalidomide, then blood was drawn at regular intervals over a 24-hour period. Thalidomide was extracted from the blood samples and subjected to HPLC analysis. A summary of some of their data is shown in Table 2.

Answer 1

Thalidomide assays have confirmed that the (S)-enantiomer is teratogenic. However, it is also known that the enantiomers of thalidomide interconvert in vivo and thus confering to the malformed fetuses. Teratogen activity not observed in animal experiments that use (R)-isomer. This result can be explained as the following:

Research has established that a fraction of thalidomide enantiomers in vivo undergoes epimerization. Then precipitation of racemic thalidomide in (R/S)-heterodimeric form occurs and so (R/S) racemic thalidomide is thought to be removed from biological processes after this racemic precipitation occurs in (R/S)-heterodimeric form. However, the enantiomerically pure thalidomide (R or S isomers, usually as the deuterium-substituted enantiomers) remains in solution and thus gives us the results of the observed biological experiment which confirms that the (S)-enantiomer is teratogenic, whereas the (R)-enantiomer is not.

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