Biotransformation of etretinate and developmental toxicity of etretin and other aromatic retinoids in teratogenesis bioassays.

Developmental toxicity of the anti-psoriatic drug etretinate (Tegison) and some features of its metabolic conversion to etretin and isoetretin were investigated in in vivo and in vitro teratogenesis bioassays. We found that a single dose of etretinate administered orally to pregnant mice on day 11 of gestation was a potent teratogen (ED50 = 26 mg/kg). Etretin (acitretin, Neotigason), given as a single dose, was about 8-fold less active as a teratogen than etretinate. A ring substituted congener of etretinate, Ro 11-4768, was essentially inactive under similar conditions. Although the mechanisms which operate to make Ro 11-4768 inactive in teratogenesis are unknown and intriguing, it is suggested that the differences between etretinate and etretin may be dependent on individual pharmacokinetic characteristics. The in vitro chondrogenesis bioassay confirmed previous reports that the presence of an acidic endgroup was necessary for suppression of chondrogenesis, and that on that basis etretin was an active inhibitor of chondrogenesis, whereas etretinate was not. Introduction of esterase into the culture medium resulted in complete hydrolysis of etretinate and a quantitative conversion to acid congeners sufficient to account for an appropriate suppression in chondrogenesis. Although limb bud cells were virtually incapable of converting etretinate to etretin in the absence of exogenous esterase, they did influence the metabolism so that in the presence of esterase, isoetretin rather than etretin was the major endproduct of etretinate hydrolysis. Since etretinate therapy endangers the conceptus for a prolonged period of time even after cessation of therapy, further studies are necessary to determine the nature and the extent of hazard posed by the storage and/or metabolism of etretinate.