ABSTRACT
Background
Methotrexate (MTX) is partially metabolized by aldehyde oxidase (AOX) in the liver and its clinical impact remains unclear. In this study, we aimed to demonstrate how AOX contributes to MTX-induced hepatotoxicity in vitro and clarify the relationship between concomitant AOX inhibitor use and MTX-associated liver injury development using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).
Methods
We assessed intracellular MTX accumulation and cytotoxicity using HepG2 cells. We used the FAERS database to detect reporting odds ratio (ROR)-based MTX-related hepatotoxicity event signals.
Results
AOX inhibition by AOX inhibitor raloxifene and siRNA increased the MTX accumulation in HepG2 cells and enhanced the MTX-induced cell viability reduction. In the FAERS analysis, the ROR for MTX-related hepatotoxicity increased with non-overlap of 95% confidence interval when co-administered with drugs with higher Imax, u (maximum unbound plasma concentration)/IC50 (half-maximal inhibitory concentration for inhibition of AOX) calculated based on reported pharmacokinetic data.
Conclusion
AOX inhibition contributed to MTX accumulation in the liver, resulting in increased hepatotoxicity. Our study raises concerns regarding MTX-related hepatotoxicity when co-administered with drugs that possibly inhibit AOX activity at clinical concentrations.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Authors’ contributions
Study design: A Moriyama, K Narumi, and M Kobayashi. Experiments and data analysis: A Moriyama, H Ueda, K Narumi, and S Asano. Writing original draft: K Narumi. All the authors have reviewed and approved the final version of the manuscript.
Data availability statement
The datasets generated and/or analyzed during the current study are available in the FAERS repository (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html).
Acknowledgments
We thank Editage (http://www.editage.jp) for English language editing.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425255.2024.2352453