The Seventh People's Hospital of Wenzhou, Wenzhou, Zhejiang, China.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
J Pharm Pharmacol. 2020 Oct;72(10):1405-1411. doi: 10.1111/jphp.13320. Epub 2020 Jun 30.
In this study, we aimed to investigate the potential interaction of apatinib and buspirone and underlying mechanism.
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 of in vitro and in vivo was 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.
Apatinib inhibited the generations of 1-PP and 6-OH buspirone dose-dependently with IC of 1.76 and 2.23 μm in RLMs, and 1.51 and 1.48 μm in HLMs, respectively. There was a mixed mechanism underlying such an inhibition effect. In rat, AUC , AUC , T and C of buspirone and 6-OH buspirone increased significantly while co-administering with apatinib, but V and CL decreased obviously while comparing group A with group B .
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.
本研究旨在探讨阿帕替尼与丁螺环酮的相互作用及其潜在机制。
采用 UPLC-MS/MS 法测定肝微粒体孵育后丁螺环酮及其主要代谢物（1-PP 和 6-OH 丁螺环酮）的浓度。此外，还进一步确定了体内外的相关性。将 Sprague Dawley 大鼠随机分为两组：A 组（20 mg/kg 丁螺环酮）和 B 组（丁螺环酮与 40 mg/kg 阿帕替尼）。采集尾静脉血，采用 UPLC-MS/MS 检测。
阿帕替尼以浓度依赖性方式抑制 1-PP 和 6-OH 丁螺环酮的生成，在 RLMs 中的 IC 分别为 1.76 和 2.23 μm，在 HLMs 中的 IC 分别为 1.51 和 1.48 μm。这种抑制作用存在混合机制。在大鼠中，与阿帕替尼合用后，丁螺环酮和 6-OH 丁螺环酮的 AUC , AUC, T 和 C 显著增加，而 V 和 CL 明显降低，与 A 组相比，B 组更为明显。
阿帕替尼以混合机制抑制丁螺环酮的 CYP450 相关代谢，并显著增加原型药物和 6-OH 丁螺环酮的血药暴露。因此，在临床联合应用阿帕替尼和丁螺环酮时应格外小心。
