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. 2023 Nov 28:14:1292354.
doi: 10.3389/fphar.2023.1292354. eCollection 2023.

Inhibitory effect of napabucasin on arbidol metabolism and its mechanism research

Jingjing Nie #  1   2 , Hailun Xia #  3 , Ya-Nan Liu  2 , Yige Yu  2 , Ren-Ai Xu  2
Affiliations

Inhibitory effect of napabucasin on arbidol metabolism and its mechanism research

Jingjing Nie et al. Front Pharmacol. .

Abstract

As a broad-spectrum antiviral, and especially as a popular drug for treating coronavirus disease 2019 (COVID-19) today, arbidol often involves drug-drug interactions (DDI) when treating critical patients. This study established a rapid and effective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to detect arbidol and its metabolite arbidol sulfoxide (M6-1) levels in vivo and in vitro. In this study, a 200 μL incubation system was used to study the inhibitory effect of the antitumor drug napabucasin on arbidol in vitro, with IC50 values of 2.25, 3.91, and 67.79 μM in rat liver microsomes (RLMs), human liver microsomes (HLMs), and CYP3A4.1, respectively. In addition, we found that the mechanism of inhibition was non-competitive inhibition in RLM and mixed inhibition in HLM. In pharmacokinetic experiments, it was observed that after gavage administration of 48 mg/kg napabucasin and 20 mg/kg arbidol, napabucasin inhibited the metabolism of arbidol in vivo and significantly changed the pharmacokinetic parameters of arbidol, such as AUC(0-t) and AUC(0-∞), in rats. We also found that napabucasin increased the AUC(0-t) and AUC(0-∞) of M6-1, the main metabolite of arbidol. This study provides a reference for the combined use of napabucasin and arbidol in clinical practice.

Keywords: CYP3A4; arbidol; drug–drug interactions; metabolism; napabucasin.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Chromatographic separation time of arbidol, arbidol sulfoxide (M6-1), and lopinavir (IS) in UPLC-MS/MS.
FIGURE 2
FIGURE 2
Michaelis constant of arbidol and half-maximal inhibitory concentration (IC50) curve of napabucasin on arbidol in RLM (A, B), HLM (C, D), and CYP3A4.1 (E, F), respectively (mean ± SD).
FIGURE 3
FIGURE 3
Primary Lineweaver–Burk plots of napabucasin inhibition on arbidol in RLM (A); intercept of the primary plot of napabucasin (B); slope of the primary plot of napabucasin (C) (mean ± SD).
FIGURE 4
FIGURE 4
Primary Lineweaver–Burk plots of napabucasin inhibition on arbidol in HLM (A); intercept of the primary plot of napabucasin (B); slope of the primary plot of napabucasin (C) (Mean ± SD).
FIGURE 5
FIGURE 5
Average plasma concentration–time curve of arbidol (A) and its metabolite M6-1 (B) in the control group (arbidol alone) and the treatment group (arbidol with napabucasin) (n = 5).
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