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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1403649
This article is part of the Research Topic Drug Metabolism and Transport: The Frontier of Personalized Medicine Volume II View all 12 articles

Inhibitory effects of calcium channel blockers nisoldipine and nimodipine on ivacaftor metabolism and their underlying mechanism

Provisionally accepted
Hailun Xia Hailun Xia Xinhao Xu Xinhao Xu *Jie Chen Jie Chen *Hualu Wu Hualu Wu *Yuxin Shen Yuxin Shen *Xiaohai Chen Xiaohai Chen Ren-ai Xu Ren-ai Xu *Wenzhi Wu Wenzhi Wu *
  • First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

The final, formatted version of the article will be published soon.

    Ivacaftor is the first potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein approved for use alone in the treatment of cystic fibrosis (CF). Ivacaftor is primarily metabolized by CYP3A4 and therefore may interact with drugs that are CYP3A4 substrates, resulting in changes in plasma exposure to ivacaftor. The study determined the levels of ivacaftor and its active metabolite M1 by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). We screened 79 drugs and 19 severely inhibited ivacaftor metabolism, particularly two cardiovascular drugs (nisoldipine and nimodipine). In rat liver microsomes (RLM) and human liver microsomes (HLM), the half-maximal inhibitory concentrations (IC 50 ) of nisoldipine on ivacaftor metabolism were 6.55 μM and 9.10 μM, respectively, and the inhibitory mechanism of nisoldipine on ivacaftor metabolism was mixed inhibition; the IC 50 of nimodipine on ivacaftor metabolism in RLM and HLM were 4.57 μM and 7.15 μM, respectively, and the inhibitory mechanism of nimodipine on ivacaftor was competitive inhibition. In pharmacokinetic experiments in rats, it was observed that both nisoldipine and nimodipine significantly altered the pharmacokinetic parameters of ivacaftor, such as AUC (0-t) and CL z/F . However, this difference may not be clinically relevant. In conclusion, this paper presented the results of studies investigating the interaction between these drugs and ivacaftor in vitro and in vivo. The objective is to provide a rationale for the safety of ivacaftor in combination with other drugs.

    Keywords: Cystic Fibrosis, Ivacaftor, Nisoldipine, Nimodipine, Drug-Drug Interaction, pharmacokinetics

    Received: 19 Mar 2024; Accepted: 04 Sep 2024.

    Copyright: © 2024 Xia, Xu, Chen, Wu, Shen, Chen, Xu and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Xinhao Xu, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
    Jie Chen, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
    Hualu Wu, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
    Yuxin Shen, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
    Ren-ai Xu, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
    Wenzhi Wu, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

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