THE HIGH-SENSITIVITY OF THE RABBIT TO THE TERATOGENIC EFFECTS OF 13-CIS-RETINOIC ACID (ISOTRETINOIN) IS A CONSEQUENCE OF PROLONGED EXPOSUREOF THE EMBRYO TO 13-CIS-RETINOIC ACID AND 13-CIS-4-OXO-RETINOIC ACID,AND NOT OF ISOMERIZATION TO ALL-TRANS-RETINOIC ACID

Previous studies suggested that the rabbit is much more susceptible to the teratogenic action of 13-cis-retinoic acid (15-cis-RA) than the m ouse or the rat, while the teratogenicity of all-trans-RA was comparab le in these species. In the present study we investigated if pharmacok inetics can explain these species- and structure-related differences. The embryotoxic and teratogenic potential of all-trans-retinoic acid ( all-trans-RA) and 13-cis-RA were evaluated in the Swiss hare rabbit af ter oral administration of daily doses of the two drugs throughout org anogenesis, from gestation day (GD) 6 to 18 (plug day = GD 0). All-tra ns-RA was given at dose levels of 0.7, 2 or 6 mg/kg body weight per da y and 13-cis-RA at 3, 7.5 or 10 mg/kg per day. The doses needed to eli cit a minimum teratogenic response were found to be 6 mg/kg per day fo r all-trans-PA and 10 mg/kg per day for 13-cis-RA. Using these doses, transplacental pharmacokinetics of all-trans- and 13-cis-RA were perfo rmed. Pregnant rabbits were treated once daily from GD 7 to 12 and pla sma and embryo samples were collected for HPLC analysis at various tim e intervals after the final dose. The main plasma metabolites of all-t rans- and 13-cis-RA were all-trans-beta-glucuronide (all-trans-RAG) an d 13-cis-4-oxo-RA, respectively. The elimination of 13-cis-RA and its metabolites from maternal plasma were much slower than of all-trans-RA resulting in accumulation of the 13-cis-isomers in plasma. Marked dif ferences in the placental transfer of the two drugs and their metaboli tes were observed. All-trans-PA and all-trans-4-oxo-RA were efficientl y transferred to the rabbit; embryo, reaching concentrations similar t o the plasma levels. On the contrary, the 13-cis-isomers reached the e mbryo to a lesser extent. Despite its limited placental transfer, a co nsiderable embryonic exposure to 13-cis-RA and 13-cis-4-oxo-RA was not iced after treatment with isotretinoin, as indicated by their area-und er-the-concentration-time-curve (AUC) values in the embryo, which were in the same range as the corresponding AUC value of all-trans-RA afte r treatment with the all-trans-isomer. Our results suggest that the hi gh sensitivity of the rabbit to the teratogenic effects of 13-cis-RA c an be attributed mainly to the 13-cis-isomers and not to isomerization to all-trans-RA. The significant exposure of the rabbit embryo to 13- cis-RA and its 4-oxo metabolite is a result of their very slow excreti on rates from the maternal organism. Furthermore, this study supports the view that embryonic AUC values should be considered as the most su itable pharmacokinetic correlate to retinoid induced teratogenesis.