School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang Province, China.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang Province, China.
Chem Biol Interact. 2019 Sep 1;310:108744. doi: 10.1016/j.cbi.2019.108744. Epub 2019 Jul 9.
The epidemic of loperamide abuse and misuse in the patients for the alternative to opioids has become an increasing worldwide concern and has led to considerations about the potential for drug-drug interactions between loperamide and other combined drugs, especially inhibitors of cytochrome P450 (CYP450) enzymes, such as axitinib. This study assessed the effects of axitinib on the metabolism of loperamide and its main metabolite N-demethylated loperamide in rats and in rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A41. The concentrations of both compounds were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The exposures (AUC, AUC and C) of loperamide and N-demethylated loperamide showed a conspicuous increase when loperamide was co-administered with axitinib. The T of loperamide increased while CLz/F decreased under the influence of axitinib. In vitro, axitinib inhibited loperamide metabolism with the IC of 18.34 μM for RLM, 1.705 μM for HLM and 1.604 μM for CYP3A41, and it was confirmed as a non-competitive inhibitor in all enzymes. Taken together, the results indicated that axitinib had an obvious inhibitory impact on loperamide metabolism both in vivo and in vitro. Thus, more attention should be paid to the concurrent use of loperamide and axitinib to reduce the risk of unexpected clinical outcomes.
洛哌丁胺滥用和误用替代阿片类药物在患者中的流行已成为全球日益关注的问题，并促使人们考虑洛哌丁胺与其他联合药物（尤其是细胞色素 P450 [CYP450] 酶抑制剂，如阿昔替尼）之间可能发生的药物相互作用。本研究评估了阿昔替尼对大鼠和大鼠肝微粒体（RLM）、人肝微粒体（HLM）和重组人 CYP3A41 中洛哌丁胺及其主要代谢物 N-去甲基洛哌丁胺代谢的影响。通过超高效液相色谱-串联质谱法（UPLC-MS/MS）测定两种化合物的浓度。当洛哌丁胺与阿昔替尼同时给药时，洛哌丁胺和 N-去甲基洛哌丁胺的浓度（AUC、AUC 和 C）显著增加。阿昔替尼的作用下，洛哌丁胺的 T 增加，而 CLz/F 降低。在体外，阿昔替尼抑制洛哌丁胺代谢，RLM、HLM 和 CYP3A41 的 IC 分别为 18.34 μM、1.705 μM 和 1.604 μM，在所有酶中均被证实为非竞争性抑制剂。综上所述，结果表明阿昔替尼在体内和体外均对洛哌丁胺的代谢具有明显的抑制作用。因此，在使用洛哌丁胺时应更加注意与阿昔替尼同时使用，以降低意外临床结果的风险。
