Physiologically Based Pharmacokinetics of Matrine in the Rat after Oral Administration of Pure Chemical and ACAPHA
Physiologically Based Pharmacokinetics of Matrine in the Rat after Oral Administration of Pure Chemical and ACAPHA
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DOI：
10.1124/dmd.108.023788
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发表时间：
2009-04-01
影响因子：
3.9
通讯作者：
Law, Francis C. P.
中科院分区：
文献类型：
--
作者：
Gao, Guanghua;Law, Francis C. P.
ACAPHA是一种在中国用于治疗人类食管癌的植物药，目前正在BC癌症机构（温哥华，BC，加拿大）作为肺癌化学预防剂进行研究。关于ACAPHA在动物中的药代动力学信息很少或没有。本研究的目的如下：检查苦参碱，在大鼠中的ACAPHA的生物活性标记物的处置动力学;开发纯苦参碱的生理学基础的药代动力学（PBPK）模型;并使用PBPK模型表征粗苦参碱在ACAPHA处理的大鼠中的吸收和清除。将纯苦参碱（15 mg/kg）或ACAPHA形式的苦参碱粗品（0.38或3.8 g/kg）通过管饲法给予大鼠。在给药后不同时间点处死大鼠。从大鼠中取出血液和主要器官，用甲苯/丁醇提取，并使用气相色谱-质谱法定量苦参碱。建立了苦参碱的11室、限流PBPK模型。PBPK模型能够很好地模拟纯苦参碱给药大鼠的经验数据。因为在ACAPHA处理的大鼠中，苦参碱粗品的吸收和清除率不能被先验地参数化，所以通过将实验数据拟合到PBPK模型来估计它们。研究结果表明，纯苦参碱被大鼠吸收和消除的速度比粗苦参碱快。此外，ACAPHA基质可显著改变苦参碱在大鼠体内的药代动力学。PBPK模型是一个有价值的工具，以获得深入了解的处置动力学的植物药。
ACAPHA, a botanical drug for the treatment of human esophageal cancer in China, is under investigation as a lung cancer chemoprevention agent at the BC Cancer Agency (Vancouver, BC, Canada). Little or no information is available on the pharmacokinetics of ACAPHA in animals. The objectives of this study were as follows: to examine the disposition kinetics of matrine, a bioactive marker of ACAPHA in the rat; to develop a physiologically based pharmacokinetic (PBPK) model for pure matrine; and to characterize the absorption and clearance of crude matrine in ACAPHA-treated rats using the PBPK model. Pure matrine (15 mg/kg) or crude matrine in the form of ACAPHA (0.38 or 3.8 g/kg) was administered to the rat by gavages. The rats were sacrificed at different time points postdosing. Blood and major organs were removed from the rat, extracted with toluene/butanol, and quantified for matrine using gas chromatography-mass spectrometry. An 11-compartment, flow-limited PBPK model of matrine was developed. The PBPK model was able to simulate closely the empirical data of rats treated with pure matrine. Because the absorption and clearance of crude matrine in ACAPHA-treated rats could not be parameterized a priori, they were estimated by fitting the experimental data to the PBPK model. Results of the study show that pure matrine is absorbed and eliminated by the rat at faster rates than crude matrine. Moreover, the ACAPHA matrix may change the pharmacokinetics of matrine in the rat significantly. The PBPK model is a valuable tool to gain insights into the disposition kinetics of a botanical drug.