Sass J O, Hartmann J, Chahoud I, Shroot B, Nau H
Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Germany.
Toxicol Lett. 1995 Jan;75(1-3):159-68. doi: 10.1016/0378-4274(94)03175-7.
Teratogenicity is a major side effect of retinoids, a class of compounds used in dermatology and oncology. The binding of retinoids to cellular retinoic acid-binding protein (CRABP) has been suggested to be important for the mechanism of retinoid embryopathy. Here data are presented on the transplacental pharmacokinetics of CD394 (4-[3-(1-adamantyl)-4-methoxybenzamido] benzoic acid) which does not bind to murine embryonic CRABP, although it is active in rat whole embryo culture and teratogenic in the rabbit in vivo. A single intragastric dose of CD394 (10 mg/kg) was administered to mice on day 11 of gestation. The extent of placental transfer of CD394, determined by HPLC, resembled more that of 13-cis-retinoic acid which also does not bind to CRABP, than that of the CRABP-binding all-trans-retinoic acid. CMax values of CD394 obtained after 1-2 h were: 1368 +/- 652 ng/ml for plasma, 203 +/- 132 ng/g for embryo and 856 +/- 563 ng/g for placenta. AUC (area-under-the-concentration-time-curve) values (0-12 h) were: 4319 ng x h/ml for plasma, 751 ng x h/g for embryo and 3163 ng x h/g for placenta. Thus, CD394 reached the embryo, although embryonic AUC values were less than one fifth of the maternal plasma AUC values. CD394 did not alter endogenous retinol concentrations in plasma, embryo, yolk sac or placenta. Our results indicate that CD394 reaches the embryo in vivo without binding to CRABP, although embryonic concentrations stayed well below plasma levels. This supports the opinion that binding to embryonic CRABP is not a prerequisite for reaching effective embryo concentrations and for the teratogenicity of retinoids.
致畸性是维甲酸类药物的主要副作用，这类化合物用于皮肤科和肿瘤学领域。维甲酸与细胞视黄酸结合蛋白（CRABP）的结合被认为对维甲酸胚胎病的机制很重要。本文给出了关于CD394（4-[3-(1-金刚烷基)-4-甲氧基苯甲酰胺基]苯甲酸）经胎盘的药代动力学数据，该化合物不与小鼠胚胎CRABP结合，尽管它在大鼠全胚胎培养中具有活性且在兔体内具有致畸性。在妊娠第11天给小鼠单次灌胃给予CD394（10 mg/kg）。通过高效液相色谱法测定，CD394的胎盘转运程度更类似于同样不与CRABP结合的13-顺式维甲酸，而非与CRABP结合的全反式维甲酸。1-2小时后获得的CD394的Cmax值为：血浆中为1368±652 ng/ml，胚胎中为203±132 ng/g，胎盘中为856±563 ng/g。AUC（浓度-时间曲线下面积）值（0-12小时）为：血浆中为4319 ng·h/ml，胚胎中为751 ng·h/g，胎盘中为3163 ng·h/g。因此，CD394能够到达胚胎，尽管胚胎的AUC值不到母体血浆AUC值的五分之一。CD394不会改变血浆、胚胎、卵黄囊或胎盘中内源性视黄醇的浓度。我们的结果表明，CD394在体内能够到达胚胎而不与CRABP结合，尽管胚胎中的浓度远低于血浆水平。这支持了一种观点，即与胚胎CRABP结合并非达到有效胚胎浓度和维甲酸致畸性的先决条件。
