Yasui H, Yamaoka K, Nakagawa T
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
J Pharm Sci. 1996 Jun;85(6):580-5. doi: 10.1021/js950531z.
The stereoselective enterohepatic circulation (EHC) and the synchronous chiral inversion of ketoprofen enantiomer in rat were evaluated by moment analysis based on the recirculatory concept. (R)-(-)- and (S)-(+)-ketoprofen were independently administered into rats, and the plasma and bile concentrations of both enantiomers were determined by a column-switching HPLC. (S)-Ketoprofen was generated by the chiral inversion from (R)-ketoprofen, whereas (R)-ketoprofen was not generated from (S)-ketoprofen. Within 30 min after intravenous administrations, the plasma time courses of R- and S-enantiomers were almost the same between rats with laparotomy and those with bile-duct cannula. After 30 min, the plasma concentrations in rats with laparotomy were significantly higher than those in rats with bile-duct cannula. The Laplace-transformed equations for stereoselective EHC and the synchronous chiral inversion were derived by means of the transfer function method on the basis of the recirculatory theory. The global moments (AUC and MRT) which were derived directly from the transformed equations were related to the local moments for the single EHC. The recirculation ratios of (R)- and (S)-ketoprofen for the single EHC were estimated to be 15.4% and 63.6%, respectively. The absorption ratios of (R)- and (S)-ketoprofen for the absorption process from the gastrointestinal tract into the systemic circulation were 87.0% and 83.8%, respectively. The biliary excretion rations of (R)- and (S)-ketoprofen for the disposition process through the systemic circulation into the bile were 17.7% and 75.8%, respectively. The chiral inversion ratio from (R)-ketoprofen into (S)-ketoprofen was 59.5%. The complicated disposition of ketoprofen, i.e., the simultaneous EHC and chiral inversion, was able to be analyzed by a moment method in a simple way.
基于再循环概念，通过矩量分析评估了大鼠体内酮洛芬对映体的立体选择性肠肝循环（EHC）和同步手性转化。将（R）-（-）-和（S）-（+）-酮洛芬分别给予大鼠，并通过柱切换HPLC测定两种对映体的血浆和胆汁浓度。（S）-酮洛芬由（R）-酮洛芬的手性转化产生，而（R）-酮洛芬不是由（S）-酮洛芬产生。静脉给药后30分钟内，开腹大鼠和胆管插管大鼠的R-和S-对映体血浆时程几乎相同。30分钟后，开腹大鼠的血浆浓度显著高于胆管插管大鼠。基于再循环理论，通过传递函数法推导了立体选择性EHC和同步手性转化的拉普拉斯变换方程。直接从变换方程导出的全局矩（AUC和MRT）与单个EHC的局部矩相关。单次EHC中（R）-和（S）-酮洛芬的再循环率分别估计为15.4%和63.6%。胃肠道吸收进入体循环过程中（R）-和（S）-酮洛芬的吸收率分别为87.0%和83.8%。体循环进入胆汁的处置过程中（R）-和（S）-酮洛芬的胆汁排泄率分别为17.7%和75.8%。（R）-酮洛芬向（S）-酮洛芬的手性转化率为59.5%。酮洛芬复杂的处置过程，即同时存在的EHC和手性转化，能够通过矩量法以简单的方式进行分析。
