Mizojiri K, Okabe H, Sugeno K, Esumi Y, Takaichi M, Miyake T, Seki H, Inaba A
Process R&D Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Arzneimittelforschung. 1997 Jan;47(1):59-69.
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. The pharmacokinetic profiles of Am-80 were studied in rats after topical application and subcutaneous administration of 14C-labeled Am-80. After topical application at a dose of 1 g ointment (0.1%)/kg to normal skin rats by the occlusive dressing technique, radioactivity was scarcely detected in the blood or plasma. In the stripped skin rats, plasma radioactivity reached the peak at 2 h and decreased with a half-life of 5.5 h. The recovery of radioactivity in the excreta and carcass amounted to 54.7% of the dose, indicating about six times higher absorption than that in the normal skin rats. After subcutaneous administration at a dose of 1 mg/kg, the maximum concentration of blood radioactivity was attained at 1-2 h and declined with a half-life of 4-5 h until 24 h. Biliary excretion was about 80% of the dose, and enterohepatic circulation was estimated to be 36.5%. Radioactivity was distributed systemically, particularly in abundance in the liver followed by adrenal gland and kidney. Elimination of radioactivity in most tissues was extremely slow and the radioactivity was detected even at 240 h after dosing. There was no gender-related difference in the profile of distribution and elimination of 14C-Am-80 in the rats. Two major metabolic pathways in rats have been postulated for Am-80; one involves the 6- or 7-hydroxylation to yield related hydroxy-Am-80 that lead to the formation of oxo-Am-80, and another involves the hydrolysis of the carboxamide bond to yield tetrahydro-tetramethyl-naphthalenylamine and terephthalic acid. Furthermore, Am-80 itself an 6- or 7-hydroxy-Am-80 were susceptible to the formation of taurine conjugates. In the plasma, unchanged Am-80 was present in a high proportion to total radioactivity, while in the urine and bile the proportion of unchanged Am-80 was low.
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）是一种新型合成维甲酸，已被证明具有强大的局部抗银屑病活性。在大鼠局部应用和皮下注射14C标记的Am-80后，研究了Am-80的药代动力学特征。通过封闭敷料技术以1 g软膏（0.1%）/kg的剂量局部应用于正常皮肤大鼠后，在血液或血浆中几乎检测不到放射性。在去表皮皮肤大鼠中，血浆放射性在2小时达到峰值，并以5.5小时的半衰期下降。排泄物和尸体中放射性的回收率为给药剂量的54.7%，表明其吸收比正常皮肤大鼠高约六倍。以1 mg/kg的剂量皮下给药后，血液放射性的最大浓度在1-2小时达到，并以4-5小时的半衰期下降直至24小时。胆汁排泄约为给药剂量的80%，肝肠循环估计为36.5%。放射性全身分布，尤其在肝脏中大量分布，其次是肾上腺和肾脏。大多数组织中放射性的消除极其缓慢，甚至在给药后240小时仍能检测到放射性。在大鼠中，14C-Am-80的分布和消除特征没有性别相关差异。已推测出大鼠体内Am-80的两条主要代谢途径；一条涉及6-或7-羟基化生成相关的羟基-Am-80，进而导致氧代-Am-80的形成，另一条涉及羧酰胺键的水解生成四氢-四甲基-萘胺和对苯二甲酸。此外，Am-80本身和6-或7-羟基-Am-80易于形成牛磺酸共轭物。在血浆中，未变化的Am-80在总放射性中占很高比例，而在尿液和胆汁中未变化的Am-80比例较低。
