手性药物布洛芬的体内药物动力学研究

【作者】 林文辉；

【导师】 崔福德； 猪爪信夫；

【作者基本信息】 沈阳药科大学 ， 药物制剂， 2004， 博士

【摘要】 布洛芬是一种广泛应用于临床的2-芳基丙酸类非甾体类抗炎药，它主要通过可逆性的抑制环氧化酶来抑制作为炎症介质的各种前列腺素的生成，从而起到解热镇痛抗炎的药理作用。在结构上，由于在其侧链上存在一个手性中心，使其具有R(-)-型和S(+)-型两个光学对映体。虽然许多体内外试验结果都表明，S(+)-布洛芬作为优对映体在抑制前列腺素生成上优于R(-)-布洛芬，然而，市售的产品中仍多数为消旋体形式。劣对映体R(-)-布洛芬可以通过形成辅酶A硫脂单向地转化为S(+)-布洛芬。了解布洛芬各对映体的体内药物动力学性质，有利于临床对布洛芬更加合理的应用，对于布洛芬的临床应用具有指导意义。 本文中首先对家兔口服芬必得和布洛芬颗粒剂后，各对映体的药物动力学性质进行了研究，考察了剂型对布洛芬对映体立体选择性体内药物动力学的影响。在家兔口服两种制剂后的整个体内过程中，S(+)-布洛芬的浓度一直大于R(-)-布洛芬，S(+)-布洛芬从体内的表观清除率较慢，由于体内Ⅰ相和Ⅱ相代谢过程都对S(+)-布洛芬具有立体选择性，从而证明由R(-)-布洛芬向S(+)-布洛芬手性转化的存在。口服两种制剂后的S／R AUC比值(颗粒剂1.85±0.49；芬必得1.78±0.61)均大于静脉注射给药后的比值(1.36±0.53)，说明可能在R(-)-布洛芬被吸收进入循环系统之前存在一部分手性转化，即系统前转化。由十二指肠分别直接给予布洛芬颗粒剂和芬必得，结果发现给予两种制剂后的S／R AUC比值均显著高于静脉注射给药，并且给予芬必得后的S／R AUC比(1.94±0.17)显著高于给予颗粒剂后的比值(1.63±0.08)，药物剂型对布洛芬的手性转化程度有一定的影响，延缓药物的吸收可以提高手性转化程度，也说明除了在肝脏可以发生手性转化外，在吸收部位(主要指肠道)也可以发生手性转化，即存在系统前转化。采用非线性同时最小二乘法，结合静脉注射给药求出了各个药物动力学参数，较客观地评价了布洛芬两对映体体内药物动力学性质的差异。 手性药物的两对映体之间在体内的各个过程中都有可能存在相互作用。在本文中通过分别给家兔静脉注射和口服消旋体布洛芬、R(-)-布洛芬和S(+)-布洛芬，对两对映体在体内过程中的相互作用进行了考察。结果发现，静脉注射后，R(-)-布洛芬和S(+)-布洛芬单独给药的情况下，比消旋体给药后的清除率大，分布容积和血清中浓度-时间曲线下面积显著减小，而这与由两对映体与血浆蛋白结合时的有相互竞争作用推断出的结果恰好相反，说明这样的结果主要与两对映体在代谢过程中的相互作用有关，代谢过程中对映体间的相互作用对它们的体内药物动力学性质的影响更大一些。本研究建立了一更多还原

【Abstract】 Ibuprofen is a 2-arylpropionic acid marketed as a non-steroidal antiinflamatory drug (NSAID) and is readily available in many dosage forms. The mode of action of the ibuprofen is via inhibition of the cyclooxygenase-mediated transformation of arachidonic acid to thromboxane and the various prostaglandins. It has two enantiomers whose pharmacological activities were significantly different. Although the S(+)-enantiomer of ibuprofen is the eutomer with respect to inhibition of prostaglandin formation, the marketed products containing ibuprofen are almost all supplied as the racemate. The R(-)-enantiomer, the distomer of ibuprofen, has been reported undergo unidirectional conversion of to the S(+)-enantiomer via formation of the acyl CoA thioester of ibuprofen.We investigated the difference of the pharmacokinetic properties after oral administration of conventional granules and Fenbid. Because of the existence of the chiral inversion, the concentration of S(+)-ibuprofen was greater than that of R(+)-ibuprofen after oral administration of two forms. And the ratio of S/R AUC after oral administration of conventional granules and Fenbid were 1.85±0.49、1.78±0.61, respectively, and they were greater than that after intravenous administration (1.36±0.53), it demonstrated that it is possible that the presystemic inversion of ibuprofen was occurred following oral administration. The chiral inversion kinetics of ibuprofen was also evaluated after intraduodenal administration of racemic ibuprofen in conventional granules form and Fenbid compared with intravenous administration in rabbits. The AUC ratios of the S(+)- and R(-)-enantiomers remained almost constant values with time up to 2h after administration of Fenbid, while those after administration of the granules increased with time. R(-)-enantiomer to S(+)-enantiomer inversion ratios after intraduodenal administration of the granules form and Fenbid, and after intravenous injection were calculated to be 1.63,1.94 and 1.19, respectively, indicating that pharmacological effects may depend on the absorption rate in rabbits.The potential interaction between two ibuprofen enantiomers was studied after更多还原