title: Neochamaejasmin B increases the bioavailability of chamaechromone coexisting in Stellera chamaejasme L. via inhibition of MRP2 and BCRP.
abstract: Chamaechromone and neochamaejasmin B (NCB) are the most abundant components in the dried roots of the toxic perennial herb Stellera chamaejasme L. and have pharmacological activities. The objective of this study was to investigate the transport mechanism of these two components in vivo and in vitro. The transport and cellular accumulation studies in Madin-Darby canine kidney (MDCK) cells overexpressing human multidrug resistance protein 2 (MRP2) or P-gp and LLC-PK1 cells overexpressing human breast cancer resistance protein (BCRP) were performed. The results showed that chamaechromone was a good substrate of MRP2 and BCRP but not a substrate of P-gp. NCB was found to be a MRP2 inhibitor in transfected cells and significantly enhanced the cellular accumulation of chamaechromone in MDCK cells overexpressing MRP2. Similar results were obtained in LLC-PK1-BCRP cells. In addition, the influence of NCB on the bioavailability of chamaechromone following their co-administration was also determined in rats. The results showed that the area under the plasma concentration-time curve and maximal plasma concentration of chamaechromone in rats were increased by 48.9% and 81.9%, respectively. The mechanism of improving the oral bioavailability of chamaechromone was attributable to the inhibition of the BCRP and MRP2-mediated efflux of chamaechromone by NCB.
authors.affiliation: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Laboratory of Natural Medicine, School of Forestry and Bio-technology, Zhejiang A&F University, Lin'an 311300, China.
authors.forename: Lanying
authors.initials: L
authors.lastname: Pan
authors.affiliation: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Zeng
authors.affiliation: Laboratory of Natural Medicine, School of Forestry and Bio-technology, Zhejiang A&F University, Lin'an 311300, China.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Huichang
authors.initials: H
authors.lastname: Bi
authors.affiliation: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Haihong
authors.initials: H
authors.lastname: Hu
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Huang
authors.affiliation: The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang 310000, China. Electronic address: louyanly@126.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lou
authors.affiliation: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address: zengsu@zju.edu.cn.
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D044946:Biflavonoids / Q000494:pharmacology*; D001682:Biological Availability; D004285:Dogs; D047309:Flavones / Q000493:pharmacokinetics*; D005452:Fluoresceins / Q000493:pharmacokinetics; D006801:Humans; D018374:LLC-PK1 Cells; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D053719:Tandem Mass Spectrometry; D029645:Thymelaeaceae / Q000378:metabolism*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D044946:Biflavonoids; D047309:Flavones; D005452:Fluoresceins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C561087:chamaechromone; C000604241:neochamaejasmin B; C085925:calcein AM
keywords: BCRP; Bioavailability; Chamaechromone; Inhibition; MRP2; Neochamaejasmin B