title: In vitro and in vivo evaluations of the P-glycoprotein-mediated efflux of dibenzoylhydrazines.
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.
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan; Otsuka Pharmaceutical Co., Ltd., Tokushima 771-0182, Japan. Electronic address: Miyata.Kenichi@otsuka.jp.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan. Electronic address: akamatsu@kais.kyoto-u.ac.jp.
authors.forename: Miki
authors.initials: M
authors.lastname: Akamatsu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001681:Biological Assay; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006834:Hydrazines / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D007275:Injections, Intravenous; D007605:Juvenile Hormones / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D008297:Male; D010575:Pesticides / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D021381:Protein Transport; D011802:Quinidine / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D013552:Swine; D053719:Tandem Mass Spectrometry; D014162:Transfection
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D006834:Hydrazines; D007605:Juvenile Hormones; D010575:Pesticides; C406712:methoxyfenozide; D011802:Quinidine; C082026:tebufenozide
keywords: Bidirectional transport assay; Brain to plasma concentration ratio; Dibenzoylhydrazines; MDR1-LLCPK1 cells; P-glycoprotein; Quinidine transport inhibition