Inhibition of Methotrexate Uptake via Organic Anion Transporters OAT1 and OAT3 by Glucuronides of Nonsteroidal Anti-inflammatory Drugs

• Iwaki Masahiro

  Department of Pharmacy, Faculty of Pharmacy, Kindai University

• Shimada Hiroaki

  Department of Pharmacy, Faculty of Pharmacy, Kindai University

• Irino Yuri

  Department of Pharmacy, Faculty of Pharmacy, Kindai University

• Take Manami

  Department of Pharmacy, Faculty of Pharmacy, Kindai University

• Egashira Sachiko

  Department of Pharmacy, Faculty of Pharmacy, Kindai University

書誌事項

タイトル別名

• Inhibition of Methotrexate Uptake <i>via</i> Organic Anion Transporters OAT1 and OAT3 by Glucuronides of Nonsteroidal Anti-inflammatory Drugs

抄録

Combination therapy of non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate (MTX) sometimes triggers adverse effects, such as liver injury, renal failure, gastrointestinal disorders, and myelosuppression, owing to the reduction of MTX clearance. Previous reports have suggested that NSAIDs inhibit renal MTX uptake via organic anion transporters (OATs) and reduced folate transporter (RFC)-1 and efflux via multidrug resistance-associated proteins (MRPs). Recently, our laboratory found inhibitory effects of NSAIDs-glucuronide (NSAIDs-Glu), a major metabolite of NSAIDs, on MRP-mediated MTX transport as a new site of interaction between MTX and NSAIDs. However, it remains unclear that whether NSAIDs-Glu inhibit renal uptake of MTX. Therefore, the present study aimed to evaluate inhibitory effects of several NSAIDs-Glu (diclofenac, R- and S-ibuprofen, R- and S-flurbiprofen, and R- and S-naproxen) on human OAT1 and OAT3-mediated MTX transport. In this study, [³H]MTX uptake was observed by using human OAT1 and OAT3-overexpressing HEK293 cells in the presence or absence of NSAIDs-Glu. All examined NSAIDs-Glu exhibited concentration-dependent inhibitory effects on MTX uptake via OAT1 and OAT3. Our results indicated that NSAIDs-Glu are more potent (5- to 15-fold) inhibitors of OAT3 than OAT1. Moreover, stereoselective inhibitory effects of NSAIDs-Glu on OATs-mediated MTX uptake were not observed, unlike on MRPs-mediated transport. These findings suggest that inhibition of OAT1 and OAT3-mediated renal uptake of MTX by plasma NSAIDs-Glu may be one of the competitive sites underlying complex drug interaction between MTX and NSAIDs.

収録刊行物

• Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ

  Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ 40 (6), 926-931, 2017

  公益社団法人 日本薬学会

キーワード

• drug interaction
• methotrexate
• non-steroidal anti-inflammatory drug
• glucuronide
• organic anion transporter

詳細情報

• CRID: 1390001204632013824
• NII論文ID: 130005687988
• NII書誌ID: AA10885497
• DOI: 10.1248/bpb.b16-00970
• ISSN: 13475215
• ISSN: 09186158
• NDL書誌ID: 028198388
• PubMed: 28566636
• Web Site: http://id.ndl.go.jp/bib/028198388
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I028198388
• Web Site: https://www.jstage.jst.go.jp/article/bpb/40/6/40_b16-00970/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2018065302
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可