Fluorothalidomide: a characterization of maternal and developmental toxicity in rabbits and mice

The expanding therapeutic uses of thalidomide (TD) are limited by its teratogenic side effects. Although the therapeutic and teratogenic effects may be stereoselectively separable, rapid in vivo racemization of the TD isomers confounds the corroboration of this distinction. Herein we evaluated the potential of fluorothalidomide (FTD), the closest structural analog of TD with stable, nonracemizing isomers, as a model compound for studying stereoselectivity in TD teratogenesis. In contrast to TD, FTD was a potent maternal and fetal toxicant in both rabbits and mice in vivo. Furthermore, FTD rapidly degraded in vivo, presumably via hydrolysis, which in vitro was up to 22-fold faster for FTD than TD. Most critically, in an established rabbit embryo culture model for TD teratogenesis, FTD did not initiate the limb bud embryopathies observed with TD. The chemical instability and strikingly different maternal and developmental toxicological profiles of FTD and TD make FTD an unsuitable compound for studying stereoselective mechanisms of TD teratogenesis.