RRC ID 51674
著者 Miyata K, Nakagawa Y, Kimura Y, Ueda K, Akamatsu M.
タイトル In vitro and in vivo evaluations of the P-glycoprotein-mediated efflux of dibenzoylhydrazines.
ジャーナル Toxicol Appl Pharmacol
Abstract 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.
巻・号 298
ページ 40-7
公開日 2016-5-1
DOI 10.1016/j.taap.2016.03.008
PII S0041-008X(16)30054-0
PMID 26995013
MeSH ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors ATP Binding Cassette Transporter, Subfamily B / genetics ATP Binding Cassette Transporter, Subfamily B / metabolism Animals Biological Assay Brain / drug effects* Brain / metabolism Cell Line Chromatography, High Pressure Liquid Dose-Response Relationship, Drug Humans Hydrazines / blood Hydrazines / pharmacokinetics* Hydrazines / toxicity Injections, Intravenous Juvenile Hormones / blood Juvenile Hormones / pharmacokinetics* Juvenile Hormones / toxicity Male Pesticides / blood Pesticides / pharmacokinetics* Pesticides / toxicity Protein Transport Quinidine / pharmacokinetics Rats, Sprague-Dawley Substrate Specificity Swine Tandem Mass Spectrometry Transfection
IF 3.585
引用数 6
リソース情報
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