Mizojiri K, Okabe H, Sugeno K, Esumi Y, Takaichi M, Harada T, Seki H, Inaba A
New Drug Research Laboratories, Shionogi & Co., Ltd., Ibaraki, Japan.
Arzneimittelforschung. 1997 Feb;47(2):201-8.
4-[5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]benzoic acid (CAS 94497-51-5, Am-80) is a new synthetic retinoid which has been shown to have a potent topical antipsoriatic activity. Placental transfer and excretion into milk after administration of 14C-Am-80 to pregnant or nursing rats were investigated in view of reproductive and developmental toxicity studies. When 14C-Am-80 was administered topically at a dose of 10 mg/kg to normal-skin pregnant rats on the 12th day of pregnancy, plasma radioactivity in the dam and fetus was detected only at low levels. However, at a dose of 1 mg/kg to the stripped-skin pregnant rats, radioactivity levels peaked at 6 h in the maternal plasma (188.7 ng eq./g) and fetus (64.6 ng eq./g) and at a dose of 10 mg/kg, the peak maternal plasma level of radioactivity and the concentration of radioactivity in the fetus up to 24 h after dosing rose about 10-fold in proportion to the increased dose. At both doses, the radioactivity level in the fetus at the peak corresponded to approximately one-third of the maternal plasma level. When 14C-Am-80 was administered subcutaneously at a dose of 1 mg/kg to pregnant rats on the 12th day of pregnancy, radioactivity in the fetus peaked at 4 h after dosing, being about one-fourth of the maternal plasma level at the same time point. Radioactivity in the fetus after subcutaneous administration of 14C-Am-80 at a dose of 1 mg/kg to pregnant rats on the 19th day of pregnancy peaked (156.4 ng eq./g) at 4 h after dosing, corresponding to approximately one-half the maternal plasma level at the same time point, and then decreased gradually. Among the fetal tissues, relatively high radioactivity was found in the liver. Whole-body autoradiography showed that in most tissues in the dam, the distribution pattern of radioactivity was similar to that in the non-pregnant rat. The concentration of radioactivity in the milk after subcutaneous administration of 14C-Am-80 at a dose of 1 mg/kg to lactating rats on the 9th day after delivery peaked at 8 h after dosing, being 94 times greater than that in the plasma. Unchanged Am-80 in the milk was largely recovered after hydrolysis of hexane extracts of the intact milk with lipase, suggesting extensive incorporation of Am-80 into the triglyceride in the milk because of its benzoic acid structure and high lipophilicity. As for radioactive metabolites which have hitherto been identified in rats, only M-6 (taurine conjugate of Am-80) and tetrahydro-tetra-methyl-naphthylamine (TTNA) were detectable in small amounts in the milk.
4-[5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)氨基甲酰基]苯甲酸（CAS 94497-51-5，Am-80）是一种新型合成类视黄醇，已被证明具有强大的局部抗银屑病活性。鉴于生殖和发育毒性研究，对怀孕或哺乳期大鼠给予14C-Am-80后，其胎盘转运及向乳汁中的排泄情况进行了研究。在怀孕第12天，对正常皮肤的怀孕大鼠局部给予剂量为10 mg/kg的14C-Am-80时，母鼠和胎儿血浆中的放射性仅在低水平被检测到。然而，对去毛皮肤的怀孕大鼠给予剂量为1 mg/kg时，母体血浆（188.7 ng当量/g）和胎儿（64.6 ng当量/g）中的放射性水平在6小时达到峰值；给予剂量为10 mg/kg时，给药后24小时内母体血浆放射性峰值水平及胎儿中的放射性浓度与剂量增加成比例地升高约10倍。在这两个剂量下，胎儿放射性水平峰值约相当于母体血浆水平的三分之一。在怀孕第12天，对怀孕大鼠皮下给予剂量为1 mg/kg的14C-Am-80时，胎儿放射性在给药后4小时达到峰值，约为同一时间点母体血浆水平的四分之一。在怀孕第19天，对怀孕大鼠皮下给予剂量为1 mg/kg的14C-Am-80后，胎儿放射性在给药后4小时达到峰值（156.4 ng当量/g），约相当于同一时间点母体血浆水平的一半，然后逐渐下降。在胎儿组织中，肝脏中的放射性相对较高。全身放射自显影显示，在母鼠的大多数组织中，放射性分布模式与未怀孕大鼠相似。在分娩后第9天，对哺乳期大鼠皮下给予剂量为1 mg/kg的14C-Am-80后，乳汁中的放射性浓度在给药后8小时达到峰值，比血浆中的放射性浓度高94倍。完整乳汁的己烷提取物用脂肪酶水解后，乳汁中未变化的Am-80大部分被回收，这表明由于其苯甲酸结构和高亲脂性，Am-80大量掺入乳汁中的甘油三酯中。至于迄今在大鼠中已鉴定出的放射性代谢物，在乳汁中仅能检测到少量的M-6（Am-80的牛磺酸结合物）和四氢-四甲基-萘胺（TTNA）。
