Contribution of Organic Anion Transporter 3 in Delayed Elimination of Methotrexate by Concomitant Administration of Febuxostat

Ikemura, Kenji; Kobayashi, Sakura; Wang, Danni et al.

Biopharmaceutics and Drug Disposition, 2025, 46(4), 165-171

アクセス数:95件（2026-02-15 23:05 集計）

固定URL: https://hdl.handle.net/11094/102958

閲覧可能ファイル 

ファイル フォーマット 利用条件 サイズ 閲覧回数 利用開始日 説明 information
BiopharmDrugDispos_46_4_165 pdf なし 864 KB 46 2025.10.31  
Creative Commons : 表示

論文情報

ファイル出力 EndNote Basic出力 Mendeley出力

タイトル
Contribution of Organic Anion Transporter 3 in Delayed Elimination of Methotrexate by Concomitant Administration of Febuxostat
著者
NRID
1000070513935 1000070513935
ORCID
0000-0003-1870-9571 0000-0003-1870-9571
researchmap permalink
Kenji_Ikemura Kenji_Ikemura
Scopus Author ID
36783115100 36783115100
著者名
Ikemura, Kenji
著者名
Kobayashi, Sakura
著者名
Wang, Danni
NRID
1000070252426 1000070252426
researchmap permalink
read0042639 read0042639
Scopus Author ID
56856467300 56856467300
著者名
Okuda, Masahiro
キーワード等
drug interaction
febuxostat
methotrexate
organic anion transporter 3
内容
Ikemura K., Kobayashi S., Wang D., et al. Contribution of Organic Anion Transporter 3 in Delayed Elimination of Methotrexate by Concomitant Administration of Febuxostat. Biopharmaceutics and Drug Disposition 46, 165 (2025); https://doi.org/10.1002/bdd.70014.
抄録
Methotrexate is an antifolate agent used for the treatment of various malignancies and is mainly secreted via human organic anion transporter 3 (hOAT3) in the proximal tubular cells. Coadministration of the xanthine oxidase inhibitor, febuxostat, in patients receiving methotrexate has been reported to be associated with an elevated risk of hematological toxicity and increased plasma methotrexate levels. Because febuxostat has an inhibitory effect against hOAT3, it may inhibit renal elimination of methotrexate via hOAT3. However, the drug interaction between methotrexate and febuxostat via hOAT3 remains to be clarified. In the present study, we investigated the effect of febuxostat on pharmacokinetics of methotrexate in rats and drug interaction between methotrexate and febuxostat using hOAT3-expressing cultured cells. In the pharmacokinetics study using rats, concomitant administration of febuxostat significantly increased plasma concentration of methotrexate and prolonged its half-life. In vitro studies showed that febuxostat inhibited hOAT3-mediated transport of methotrexate in a concentration-dependent manner. Dixon plot indicated that inhibitory constant value of febuxostat against methotrexate transport via hOAT3 was 0.63 ± 0.01 μM. Moreover, the inhibitory effect of febuxostat was of noncompetitive type. Taken together, these results suggest that concomitant administration of febuxostat delayed elimination of methotrexate, at least in part, by noncompetitive inhibition of hOAT3-mediated methotrexate transport at clinical concentrations. The findings of this study provide novel information on drug interactions associated with febuxostat.
出版者
John Wiley and Sons Ltd
収録物名
Biopharmaceutics and Drug Disposition
巻(号)
46(4)
ページ
165-171
刊行年月
2025-08-25
言語
英語
ハンドルURL
https://hdl.handle.net/11094/102958
PISSN
01422782
eISSN
1099081X
関連情報 (isIdenticalTo)
DOI (出版社版)
https://doi.org/10.1002/bdd.70014
アクセス権
open access
権利情報
This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ
Version of Record
カテゴリ
学術雑誌論文 Journal Article