| RRC ID |
51674
|
| Author |
Miyata K, Nakagawa Y, Kimura Y, Ueda K, Akamatsu M.
|
| Title |
In vitro and in vivo evaluations of the P-glycoprotein-mediated efflux of dibenzoylhydrazines.
|
| Journal |
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.
|
| Volume |
298
|
| Pages |
40-7
|
| Published |
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
|
| Times Cited |
6
|
| Resource |
| Human and Animal Cells |
LLC-GA5-CoL150(RCB0871) |
