The high sensitivity of the rabbit to the teratogenic effects of 13-cis-retinoic acid (isotretinoin) is a consequence of prolonged exposure of the embryo to 13-cis-retinoic acid and 13-cis-4-oxo-retinoic acid, and not of isomerization to all-trans-retinoic acid

Abstract

Previous studies suggested that the rabbit is much more susceptible to the teratogenic action of 13-cis-retinoic acid (13-cis-RA) than the mouse or the rat, while the teratogenicity of all-trans-RA was comparable in these species. In the present study we investigated if pharmacokinetics 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 after oral administration of daily doses of the two drugs throughout organogenesis, from gestation day (GD) 6 to 18 (plug day = GD 0). All-trans-RA was given at dose levels of 0.7, 2 or 6 mg/kg body weight per day and 13-cis-RA at 3, 7.5 or 10 mg/kg per day. The doses needed to elicit a minimum teratogenic response were found to be 6 mg/kg per day for all-trans-RA and 10 mg/kg per day for 13-cis-RA. Using these doses, transplacental pharmacokinetics of all-trans- and 13-cis-RA were performed. Pregnant rabbits were treated once daily from GD 7 to 12 and plasma and embryo samples were collected for HPLC analysis at various time intervals after the final dose. The main plasma metabolites of all-trans- and 13-cis-RA were all-trans-beta-glucuronide (all-trans-RAG) and 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 differences in the placental transfer of the two drugs and their metabolites were observed. All-trans-RA and all-trans-4-oxo-RA were efficiently transferred to the rabbit embryo, reaching concentrations similar to the plasma levels. On the contrary, the 13-cis-isomers reached the embryo to a lesser extent. Despite its limited placental transfer, a considerable embryonic exposure to 13-cis-RA and 13-cis-4-oxo-RA was noticed after treatment with isotretinoin, as indicated by their area-under-the-concentration-time-curve (AUC) values in the embryo, which were in the same range as the corresponding AUC value of all-trans-RA after treatment with the all-trans-isomer.(ABSTRACT TRUNCATED AT 400 WORDS)

Mechanisms regulating toxicant disposition to the embryo during early pregnancy: An interspecies comparison

“…Nevertheless, embryo:maternal AUC ratios are only 0.05-0.08 in rabbits (Eckoff et al, 1994;Tzimas et al, 1994), which are comparable to the ratios achieved in rodents. It is possible that the greater sensitivity of the rabbit to this compound is due to the long half life of 13-cis-retinoic acid (10 hr) in this species.…”

Percutaneous Absorption, Excretion and Metabolism of All-<i>trans</i>-Retinoyl β-Glucuronide and of AII-<i>trans</i>-Retinoic Acid in the Rat

“…Thus, these drugs are not prescribed to women who are pregnant or might become pregnant during therapy [1,[13][14][15][16][17], All-/ram-retinoyl (3-glucuronide (RAG), first identified as a biliary metabolite of vita min A [18,19], occurs endogenously in hu man blood [20], RAG and its 13-m-isomer have been identified as major biliary metabo lites of RA in the rat [21][22][23], Following administration of all-tram, 13-d,v-and 9-cis-RA. their respective p-glucuronides have been characterized as major plasma metabolites in the monkey [24][25][26], in the rat [27,28], in the mouse [27,29], in the rabbit [30], and in the human [20,25], RAG, like RA, shows high biological activity in enhancing the growth of vitamin A-deficient rats [31,32] and in induc ing the differentiation of HL-60 [33][34][35][36] and GBA-HAN-1C cells [37], In contrast. RAG is much less cytotoxic [33][34][35][36][37] and embryotoxic than tRA [38], Orally administered RAG is not teratogenic in pregnant Sprague-Dawley rats [39], Topically applied RAG, at concen trations *1.2% in cream, is as efficacious as RA in the treatment of acne [40], but concen trations as high as 2.4% RAG in cream do not cause the adverse side effects associated with topical RA (0.1 %) treatment [40],…”

Astonishing diversity of natural surfactants: 3. Carotenoid glycosides and isoprenoid glycolipids

“…They are naturally occurring biologically active metabolites of vitamin A and are found in freshwater and marine fish and in mammals (92)(93)(94). Retinoyl-β-glucuronide 105 has been characterized as a metabolite of vitamin A in the plasma of humans (95) and in the plasma and tissues of several animals, such as the monkey (96), mouse (97), and rabbit (98).…”