2016年5月
In vitro and in vivo evaluations of the P-glycoprotein-mediated efflux of dibenzoylhydrazines
TOXICOLOGY AND APPLIED PHARMACOLOGY
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- 巻
- 298
- 号
- 開始ページ
- 40
- 終了ページ
- 47
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1016/j.taap.2016.03.008
- 出版者・発行元
- ACADEMIC PRESS INC ELSEVIER SCIENCE
P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter family. It actively transports a wide variety of compounds out of cells to protect humans from xenobiotics. Thus, determining whether chemicals are substrates and/or inhibitors of P-gp is important in risk assessments of pharmacokinetic interactions among chemicals because P-gp-mediated transport processes play a significant role in their absorption and disposition. We previously reported that dibenzoylhydrazines (DBHs) such as tebufenozide and methoxyfenozide (agrochemicals) stimulated P-gp ATPase activity. However, it currently remains unclear whether these derivatives are transport substrates of P-gp and inhibit transport of other chemicals by P-gp.
In the present study, in order to evaluate the interactions of DBHs with other chemicals in humans, we determined whether DBHs are P-gp transport substrates using both the in vitro bidirectional transport assay and the in vivo study of rats. In the in vivo study, we investigated the influence of P-gp inhibitors on the brain to plasma ratio of methoxyfenozide in rats. We also examined the inhibitory effects of DBHs on quinidine (a P-gp substrate) transport by P-gp in order to ascertain whether these derivatives are inhibitors of P-gp. Based on the results, DBHs were concluded to be weak P-gp transport substrates and moderate P-gp inhibitors. However, the risk of DBHs caused by interaction with other chemicals including drugs was considered to be low by considering the DBHs' potential as the substrates and inhibitors of P-gp as well as their plasma concentrations as long as DBHs are properly used. (C) 2016 Elsevier Inc. All rights reserved.
In the present study, in order to evaluate the interactions of DBHs with other chemicals in humans, we determined whether DBHs are P-gp transport substrates using both the in vitro bidirectional transport assay and the in vivo study of rats. In the in vivo study, we investigated the influence of P-gp inhibitors on the brain to plasma ratio of methoxyfenozide in rats. We also examined the inhibitory effects of DBHs on quinidine (a P-gp substrate) transport by P-gp in order to ascertain whether these derivatives are inhibitors of P-gp. Based on the results, DBHs were concluded to be weak P-gp transport substrates and moderate P-gp inhibitors. However, the risk of DBHs caused by interaction with other chemicals including drugs was considered to be low by considering the DBHs' potential as the substrates and inhibitors of P-gp as well as their plasma concentrations as long as DBHs are properly used. (C) 2016 Elsevier Inc. All rights reserved.
- リンク情報
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- DOI
- https://doi.org/10.1016/j.taap.2016.03.008
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/26995013
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000374429200005&DestApp=WOS_CPL
- URL
- http://europepmc.org/abstract/med/26995013
- URL
- http://orcid.org/0000-0003-2980-6078
- ID情報
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- DOI : 10.1016/j.taap.2016.03.008
- ISSN : 0041-008X
- eISSN : 1096-0333
- ORCIDのPut Code : 28392448
- PubMed ID : 26995013
- Web of Science ID : WOS:000374429200005