Hara Takumi, Arima Hidetoshi, Hirayama Fumitoshi, Uekama Kaneto
Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.
J Pharm Sci. 2006 Aug;95(8):1771-82. doi: 10.1002/jps.20655.
The effect of bile acids on bioavailability of FPFS-410 (2-(N-Cyanoimino)-5-{(E)-4-styrylbenzylidene}-4-oxothiazolidine) after oral administration of the drug and its 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) complex was investigated. The complexation with HP-beta-CyD increased the oral bioavailability of FPFS-410 in normal rats in a HP-beta-CyD concentration-dependent manner, compared with that of drug alone. In bile duct-cannulated rats, bile acid concentrations in pylic serum and biliary were decreased to 18% and 14% of sham-operated rats, respectively. After oral administration of the HP-beta-CyD complex, the plasma levels of FPFS-410 were lower in bile duct-cannulated rats than in sham-operated rats up to 1 h, however, this order reversed from 2 to 12 h. The plasma levels of M1, a dominant metabolite of FPFS-410 in rats, significantly decreased until 2 h after administration of the complex in bile duct-cannulated rats, compared with in sham-operated rats. Bioconversion of FPFS-410 to M1 and CYP3A2 expression in the liver was markedly lowered by bile duct-cannulation. Bile duct-cannulation did not, however, affect the serum levels of estradiol. These results suggest that bile acids have a pivotal role for bioavailability of FPFS-410 after oral administration of the FPFS-410 complex with HP-beta-CyD through CYP3A2 activity in liver of rats.
研究了胆汁酸对药物FPFS-410（2-(N-氰基亚氨基)-5-{(E)-4-苯乙烯基亚苄基}-4-氧代噻唑烷）及其2-羟丙基-β-环糊精（HP-β-CyD）复合物口服给药后生物利用度的影响。与单独给药相比，HP-β-CyD的络合作用以HP-β-CyD浓度依赖性方式提高了正常大鼠中FPFS-410的口服生物利用度。在胆管插管大鼠中，门静脉血清和胆汁中的胆汁酸浓度分别降至假手术大鼠的18%和14%。口服HP-β-CyD复合物后，胆管插管大鼠中FPFS-410的血浆水平在1小时内低于假手术大鼠，但在2至12小时后这种顺序发生逆转。与假手术大鼠相比，在胆管插管大鼠中，给予复合物后直至2小时，大鼠中FPFS-410的主要代谢产物M1的血浆水平显著降低。胆管插管显著降低了FPFS-410向M1的生物转化以及肝脏中CYP3A2的表达。然而，胆管插管并未影响雌二醇的血清水平。这些结果表明，胆汁酸在大鼠肝脏中通过CYP3A2活性对口服给予FPFS-410与HP-β-CyD复合物后的生物利用度起关键作用。
