The effect of apatinib on pharmacokinetic profile of buspirone bothin vivoandin vitro
The effect of apatinib on pharmacokinetic profile of buspirone bothin vivoandin vitro
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DOI：
10.1111/jphp.13320
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发表时间：
2020-06-30
影响因子：
3.3
通讯作者：
Qian, Jian-chang
中科院分区：
文献类型：
--
作者：
Zhang, Xiao-dan;Li, Ying-hui;Qian, Jian-chang
目的 在本研究中，我们旨在探讨阿帕替尼和丁螺环酮的潜在相互作用及其潜在机制。方法采用UPLC-MS/MS法测定与肝微粒体孵育后的丁螺环酮及其主要代谢物（1-PP和6-OH丁螺环酮）的浓度。并且进一步确定了体外与体内的联系。 Sprague Dawley 大鼠被随机分为两组：A 组（20 mg/kg 丁螺环酮）和 B 组（丁螺环酮 vs 40 mg/kg 阿帕替尼）。采集尾静脉血并进行UPLC-MS/MS检测。主要发现 阿帕替尼剂量依赖性地抑制 1-PP 和 6-OH 丁螺环酮的生成，IC(50) 分别为 1.76 和 2.23 mu min RLM，以及 1.51 和 1.48 mu min HLM。这种抑制作用背后存在着一种混合机制。大鼠中，与阿帕替尼合用时，丁螺环酮和6-OH丁螺环酮的AUC((0-)(t)())、AUC((0-无穷大))、T(max)和C(max)显着增加，但与A组和B组相比，V(z/F)和CL(z/F)明显降低。结论 阿帕替尼以混合机制抑制丁螺环酮基于 CYP450 的代谢，并显着增加原型药和 6-OH 丁螺环酮的血液暴露。因此，临床上阿帕替尼与丁螺环酮合用时应格外谨慎。
Objective In this study, we aimed to investigate the potential interaction of apatinib and buspirone and underlying mechanism. Methods UPLC-MS/MS assay was applied to determine the concentrations of buspirone and its main metabolites (1-PP and 6-OH buspirone) after incubated with liver microsomes. Moreover, the connection ofin vitroandin vivowas further determined. Sprague Dawley rats were randomly divided into two groups: group A (20 mg/kg buspirone) and group B (buspirone vs 40 mg/kg apatinib). Tail vein blood was collected and subjected to the UPLC-MS/MS detection. Key findings Apatinib inhibited the generations of 1-PP and 6-OH buspirone dose-dependently with IC(50)of 1.76 and 2.23 mu min RLMs, and 1.51 and 1.48 mu min HLMs,respectively. There was a mixed mechanism underlying such an inhibition effect. In rat, AUC((0-)(t)()), AUC((0-infinity)),T(max)andC(max)of buspirone and 6-OH buspirone increased significantly while co-administering with apatinib, butV(z/F)and CL(z/F)decreased obviously while comparing group A with group B . Conclusions Apatinib suppresses the CYP450 based metabolism of buspirone in a mixed mechanism and boosted the blood exposure of prototype drug and 6-OH buspirone dramatically. Therefore, extra caution should be taken when combining apatinib with buspirone in clinic.