Pharmacokinetics, tissue distribution, and placental permeability of all-trans- and 13-cis-N-ethyl retinamides in pregnant hamsters.

Retinamides have clinical applications in therapy of dermatologic disease, have cancer chemopreventive/chemotherapeutic activities, and possess larger therapeutic ratios than their acidic congeners. The N-ethyl-all-trans-retinamide (NERA) and its 13-cis congener (CNERA) failed to induce terata in hamsters, but an equivalent oral dose of all-trans- or 13-cis-retinoic acid was associated with a significant teratogenic response. Following intubation of 11.4 mg/kg of [3H]NERA or [3H]CNERA to pregnant hamsters during a sensitive stage of development, radioactivity accumulated in maternal bladder and liver. Although plasma concentrations of the parent retinamides declined to nondetectable levels within 12 hr of dosing, near-peak concentrations of retinamide metabolites persisted in maternal plasma until termination of the study (96 hr). Cis/trans isomerization of each retinamide at C13 occurred, but only 15-20% of the total dose could be accounted for as parent retinamide and its C13 isomer. The retinamides were not metabolized to detectable concentrations of circulating all-trans- or 13-cis-retinoic acid. Although the label associated with the retinamides and their biotransformation products crossed the placenta, there was no evidence for preferential accumulation in embryonic or fetal tissues. The results presented here show that the reduced teratogenic potency of retinamides compared to acidic retinoids cannot be ascribed to reduce placental transfer.