| アブストラクト | 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 I(max, u) (maximum unbound plasma concentration)/IC(50) (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. |
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| ジャーナル名 | Expert opinion on drug metabolism & toxicology |
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| 投稿日 | 2024/5/6 |
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| 投稿者 | Moriyama, Ayako; Ueda, Hinata; Narumi, Katsuya; Asano, Shuho; Furugen, Ayako; Saito, Yoshitaka; Kobayashi, Masaki |
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| 組織名 | Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences,;Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.;Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical;Sciences, Hokkaido University, Sapporo, Japan.;Department of Clinical Pharmaceutics & Therapeutics, Faculty of Pharmaceutical;Sciences, Hokkaido University of Science, Sapporo, Japan. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/38706380/ |
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