Chong Yae Eun, Chiang Manting, Deshpande Kiran, Haroutounian Simon, Kagan Leonid, Lee Jong Bong
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
Division of Clinical and Translational Research and Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA.
Biomed Chromatogr. 2019 Nov;33(11):e4653. doi: 10.1002/bmc.4653. Epub 2019 Sep 1.
Ondansetron, a widely used antiemetic agent, is a P-glycoprotein (P-gp) substrate and therefore expression of P-gp at the blood-brain barrier limits its distribution to the central nervous system (CNS), which was observed to be reversed by coadministration with P-gp inhibitors. Tariquidar is a potent and selective third-generation P-gp inhibitor, and coadministration with ondansetron has shown improved ondansetron distribution to the CNS. There is currently no reported bioanalytical method for simultaneously quantifying ondansetron with a third-generation P-gp inhibitor. Therefore, we aimed to develop and validate a method for ondansetron and tariquidar in rat and human plasma samples. A full validation was performed for both ondansetron and tariquidar, and sample stability was tested under various storage conditions. To demonstrate its utility, the method was applied to a preclinical pharmacokinetic study following coadministration of ondansetron and tariquidar in rats. The presented method will be valuable in pharmacokinetic studies of ondansetron and tariquidar in which simultaneous determination may be required. In addition, this is the first report of a bioanalytical method validated for quantification of tariquidar in plasma samples.
昂丹司琼是一种广泛使用的止吐药，是P-糖蛋白（P-gp）的底物，因此血脑屏障处P-gp的表达限制了其向中枢神经系统（CNS）的分布，研究发现与P-gp抑制剂合用可逆转这种情况。 tariquidar是一种强效且选择性的第三代P-gp抑制剂，与昂丹司琼合用已显示可改善昂丹司琼在中枢神经系统的分布。目前尚无同时定量测定昂丹司琼与第三代P-gp抑制剂的生物分析方法。因此，我们旨在开发并验证一种用于测定大鼠和人血浆样品中昂丹司琼和tariquidar的方法。对昂丹司琼和tariquidar均进行了全面验证，并在各种储存条件下测试了样品稳定性。为证明其实用性，该方法应用于大鼠同时给予昂丹司琼和tariquidar后的临床前药代动力学研究。所提出的方法在可能需要同时测定的昂丹司琼和tariquidar的药代动力学研究中将具有重要价值。此外，这是第一篇关于验证血浆样品中tariquidar定量的生物分析方法的报告。
