Reference - Detail
| RRC ID | 82567 |
|---|---|
| Author | Moriyama A, Ueda H, Narumi K, Asano S, Furugen A, Saito Y, Kobayashi M. |
| Title | Contribution of aldehyde oxidase to methotrexate-induced hepatotoxicity: in vitro and pharmacoepidemiological approaches. |
| Journal | Expert Opin Drug Metab Toxicol |
| 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. |
| Volume | 20(5) |
| Pages | 399-406 |
| Published | 2024-5-1 |
| DOI | 10.1080/17425255.2024.2352453 |
| PMID | 38706380 |
| MeSH | Adverse Drug Reaction Reporting Systems* Aldehyde Oxidase* / metabolism Antimetabolites, Antineoplastic / administration & dosage Antimetabolites, Antineoplastic / adverse effects Cell Survival / drug effects Chemical and Drug Induced Liver Injury* / etiology Hep G2 Cells Humans Inhibitory Concentration 50 Methotrexate* / administration & dosage Methotrexate* / adverse effects RNA, Small Interfering / administration & dosage RNA, Small Interfering / pharmacology United States United States Food and Drug Administration |
| IF | 3.47 |
| Resource | |
| Human and Animal Cells | Hep G2 |