Study on the pharmacokinetics profiles of polyphyllin I and its bioavailability enhancement through co-administration with P-glycoprotein inhibitors by LC-MS/MS method.
Study on the pharmacokinetics profiles of polyphyllin I and its bioavailability enhancement through co-administration with P-glycoprotein inhibitors by LC-MS/MS method.
复制标题
DOI：
10.1016/j.jpba.2014.12.002
复制
发表时间：
2015-03
影响因子：
3.4
通讯作者：
He Zhu;Si-Can Zhu;S. Shakya;Q. Mao;C. Ding;M. Long;Song-Lin Li
中科院分区：
文献类型：
--
作者：
He Zhu;Si-Can Zhu;S. Shakya;Q. Mao;C. Ding;M. Long;Song-Lin Li
多叶一枝花皂苷（Polyphyllin I，PPI）是一种很有前途的天然抗肿瘤药物。虽然PPI的抗癌活性已得到充分证明，但关于药代动力学和生物利用度的信息有限。本研究建立了一系列可靠、快速的液相色谱-串联质谱法，并成功应用于大鼠血浆、细胞培养液和细胞匀浆中PPI的测定。PPI在大鼠体内的药代动力学研究结果表明，PPI在50 mg/kg剂量时消除缓慢，口服生物利用度较低（约0.62%），与维拉帕米（VPL）和环孢素A（CYA）合用后，PPI的口服生物利用度分别由0.62%提高到3.52%和3.79%。此外，体外研究表明，在Caco-2细胞中存在VPL和CYA时，PPI的外排率从12.5降低至2.96和2.22，细胞内浓度分别增加5.8倍和5.0倍。这些结果表明，PPI口服生物利用度低，P-gp外排严重阻碍PPI的外排，抑制P-gp可提高其生物利用度。
Polyphyllin I (PPI), one of the steroidal saponins inParis polyphylla, is a promising natural anticancer candidate. Although the anticancer activity of PPI has been well demonstrated, information regarding the pharmacokinetics and bioavailability is limited. In this study, a series of reliable and rapid liquid chromatography–tandem mass spectrometry methods were developed and successfully applied to determinate PPI in rat plasma, cell incubation media and cell homogenate. Then the pharmacokinetics of PPI in rats was studied and the result revealed that PPI was slowly eliminated with low oral bioavailability (about 0.62%) at a dose of 50 mg/kg, and when co-administrated with verapamil (VPL) and cyclosporine A (CYA), the oral bioavailability of PPI could increase from 0.62% to 3.52% and 3.79% respectively. In addition, in vitro studies showed that with the presence of VPL and CYA in Caco-2 cells, the efflux ratio of PPI decreased from 12.5 to 2.96 and 2.22, and the intracellular concentrations increased 5.8- and 5.0-fold respectively. These results demonstrated that PPI, with poor oral bioavailability, is greatly impeded byP-gp efflux, and inhibition ofP-gp can enhance its bioavailability.