Concomitant febuxostat enhances methotrexate-induced hepatotoxicity by inhibiting breast cancer resistance protein.
|アブストラクト||Methotrexate (MTX) is an antifolate agent used for the treatment of various malignancies and is eliminated by breast cancer resistance protein (BCRP). Because febuxostat (FBX) is known to inhibit BCRP activity, FBX might exacerbate MTX-related adverse effects. In this study, we examined the drug-drug interaction between FBX and MTX in BCRP-expressing membrane vesicles. Moreover, we retrospectively investigated the impact of FBX on MTX-related adverse effects in 38 patients (144 cycles) receiving high-dose MTX therapy (HDMTX). The Food and Drug Administration Adverse Event Reporting System (FAERS) database and human hepatocellular carcinoma cell line HepG2 cells were used to evaluate the effects of FBX on MTX-induced hepatotoxicity. In the membrane vesicle study, FBX significantly inhibited BCRP-mediated transport of MTX. Concomitant FBX significantly increased the incidence of hepatotoxicity, but not of nephrotoxicity and hematological toxicity in patients receiving HDMTX. FAERS database analyses revealed that the reporting odds ratio of FBX for MTX-induced hepatotoxicity was 4.16 (95% CI: 2.89-5.98). Co-incubated FBX significantly decreased the cell viability and increased cytotoxicity in MTX-treated HepG2 cells. These findings suggest that concomitant FBX enhances MTX-induced hepatotoxicity by inhibiting hepatic BCRP. These findings provide important information for the safe management of HDMTX therapy in clinical settings.|
|投稿者||Ikemura, Kenji; Hiramatsu, Shun-Ichi; Shinogi, Yuri; Nakatani, Yusuke; Tawara, Isao; Iwamoto, Takuya; Katayama, Naoyuki; Okuda, Masahiro|
|組織名||Department of Pharmacy, Mie University Hospital, Tsu, Mie, 514-8507, Japan.;email@example.com.;Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate;School of Medicine, Tsu, Mie, 514-8507, Japan.;Department of Hematology and Oncology, Mie University Graduate School of;Medicine, Tsu, Mie, 514-8507, Japan.;Department of Pharmacy, Osaka University Hospital, Suita, Osaka, 565-0871, Japan.|