title: In vitro to in vivo evidence of the inhibitor characteristics of Schisandra lignans toward P-glycoprotein.
abstract: Concomitant administration of herbal medicines with drugs that are P-glycoprotein (P-gp) substrates may produce significant herb-drug interactions. The purpose of this study was to evaluate the effects of Schisandra lignans extract (SLE) on P-gp thoroughly in vitro and in vivo, and to investigate the possible P-gp-based herb-drug interactions. In the in vitro experiments, the effect of SLE on the uptake and transport for P-gp substrates in Caco-2, LLC-PK1 and L-MDR1 cells were carefully investigated. Verapamil, a known P-gp inhibitor, was used as a positive control drug. Results shown that, 10 μM verapamil and SLE (0.5, 2.0, and 10.0 μg/ml) were observed to significantly enhance the uptake and inhibit the efflux ratio of P-gp substrates in Caco-2 and L-MDR1 cells. In vivo experiments showed that single-dose SLE at 500 mg/kg could increase the area under the plasma concentration time curve of digoxin and vincrisine significantly without affecting terminal elimination half-time. Long-term treatment with SLE for continuous 10 days could also increase the absorption of P-gp substrates with greatly down regulation of P-gp expression in rat intestinal and brain tissues. In conclusion, SLE was a strong P-gp inhibitor, which indicated a potential herb-drug interaction when SLE was co-administered with P-gp substrate drugs.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. liangyan@cpu.edu.cn
authors.forename: Yan
authors.initials: Y
authors.lastname: Liang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jingwei
authors.initials: J
authors.lastname: Zhang
authors.forename: Yanna
authors.initials: Y
authors.lastname: Liu
authors.forename: Tianye
authors.initials: T
authors.lastname: Guan
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Xing
authors.forename: Tai
authors.initials: T
authors.lastname: Rao
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhou
authors.forename: Kun
authors.initials: K
authors.lastname: Hao
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Guang-ji
authors.initials: GJ
authors.lastname: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D018938:Caco-2 Cells; D004077:Digoxin / Q000378:metabolism; D041743:Herb-Drug Interactions; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D017705:Lignans / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D032141:Schisandra / Q000737:chemistry*; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017705:Lignans; D010936:Plant Extracts; D014750:Vincristine; D004077:Digoxin; D014700:Verapamil
keywords: AP; AUC; BL; C(max); CL; CMC-Na; DDI; DGX; HBSS; HMs; HPLC; Hank's balanced salt solution; Herb–drug interaction; Inhibitor; LC/MS; LC–IT-TOF/MS; P-glycoprotein; P-gp; SLE; Schisandra lignans extract; TBS-T; Tris-buffered saline-Tween 20; VCR; apical; basolateral; clearance; digoxin; drug–drug interaction; half-life time; herbal medicines; high-performance liquid chromatography; liquid chromatography combined hybrid ion trap time-of-flight mass spectrometry; liquid chromatography combined mass spectrometry; maximum plasma concentration; sodium carboxymethyl cellulose; t(1/2); the area under the concentration–time curve; vincrisine