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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.

Background: Although several treatment and screening methods have been tried, the incidence of patients with end-stage renal disease (ESRD) on renal replacement therapy (RRT) continues to increase worldwide. By making a detailed analysis of the major primary renal diseases, we found there have been some favorable effects in the incidence rate of ESRD recently in Japan., Methods: A total of 339,478 patients in Japan and 909,591 patients in the United States started RRT between 1983 and 1999. We compared trends of average age and incidence rate in each age group with major primary renal diseases and in racial groups after adjusting for general population aging by using a linear regression analysis., Results: All trends in ESRD incidence rates among Japanese, US total, US white, and US black patients showed significant increases (P < 0.001). A significant positive linear relationship between year and mean age at start of RRT also was observed (P < 0.001). After adjustment for general population aging, the mean age increment in Japanese patients with glomerulonephritis was increased significantly, and the proportion of Japanese patients who had glomerulonephritis and were younger than 45 years was decreased, but this decrement was not observed in US patients with glomerulonephritis., Conclusion: The reduced number of new patients with ESRD with glomerulonephritis might be caused by early detection and early referral to nephrologists as a result of the Japanese urinalysis-screening program. To reduce the ESRD population, it will be necessary to establish more effective treatment methods to delay exacerbation of progressive renal diseases.