Concomitant febuxostat enhances methotrexate-induced hepatotoxicity by inhibiting breast cancer resistance protein

Kenji Ikemura,Yuri Shinogi,Naoyuki Katayama,Yusuke Nakatani,Takuya Iwamoto,Isao Tawara,Masahiro Okuda,Shun-Ichi Hiramatsu

doi:10.1038/s41598-019-56900-2

Kenji Ikemura, Yuri Shinogi + Show 6 more

Open Access

https://doi.org/10.1038/s41598-019-56900-2

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Abstract

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.

Highlights

Methotrexate (MTX) is an antifolate agent used for the treatment of various malignancies and is eliminated by breast cancer resistance protein (BCRP)
It has been reported that co-administration of proton pump inhibitors (PPIs) and non-steroidal anti-inflammatory drugs (NSAIDs), which are well-investigated as inhibitors of OATs, MRP2, and BCRP, delay the elimination half-life of MTX in patients receiving HDMTX16–19, which may lead to the increased risk of severe adverse effects
The impact of concomitant FBX on the development of MTX-related adverse effects was examined by retrospective chart review of the hospitalized patients who received high-dose MTX therapy (HDMTX) therapy, database analysis using Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), and an in vitro study using human hepatocellular carcinoma cell line (HepG2 cells)

Summary

Introduction

Methotrexate (MTX) is an antifolate agent used for the treatment of various malignancies and is eliminated by breast cancer resistance protein (BCRP). 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. It has been reported that co-administration of proton pump inhibitors (PPIs) and non-steroidal anti-inflammatory drugs (NSAIDs), which are well-investigated as inhibitors of OATs, MRP2, and BCRP, delay the elimination half-life of MTX in patients receiving HDMTX16–19, which may lead to the increased risk of severe adverse effects. The impact of concomitant FBX on the development of MTX-related adverse effects was examined by retrospective chart review of the hospitalized patients who received HDMTX therapy, database analysis using Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), and an in vitro study using human hepatocellular carcinoma cell line (HepG2 cells)

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