title: Organic anion-transporting polypeptides contribute to the hepatic uptake of berberine.
abstract: 1. The purpose of this study was to investigate the mechanism of hepatic uptake of berberine. Berberine accumulation in hepatocytes was found to be highly dependent on active uptake, which could not be explained by liver organic cation transporter (OCT) alone. 2. Our studies indicated that berberine uptake was significantly suppressed by rifampicin, cyclosporine A and glycyrrhizic acid, which act as specific inhibitors of different Oatp isoforms (Oatp1a1, Oatp1a4 and Oatp1b2) in rat hepatocytes. The combination of OCT and OATP inhibitors further reduced berberine accumulation in both rat and human hepatocytes. The uptake of berberine could be increased in human HEK293-OATP1B3 but not in OATP1B1-transfected HEK 293 cells. 3. Rifampicin could reduce the berberine liver extraction ratio (ER) and double its concentration in the effluent in isolated rat livers. Further in vivo study indicated that berberine plasma exposure could be significantly increased by co-administration of the OATP inhibitor rifampicin or the substrate rosuvastatin. 4. In conclusion, this study demonstrated that both OCT and OATP contribute to the accumulation of berberine in the liver. OATPs may have important roles in berberine liver disposition and potential clinically relevant drug--drug interactions.
authors.affiliation: a Institute of Life Sciences, Jiangsu University , Zhenjiang , P.R. China and.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: b Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P.R. China.
authors.forename: Zhi-Tao
authors.initials: ZT
authors.lastname: Wu
authors.affiliation: b Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P.R. China.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Ma
authors.affiliation: b Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P.R. China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Ni
authors.affiliation: b Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P.R. China.
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Lin
authors.affiliation: b Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P.R. China.
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.affiliation: a Institute of Life Sciences, Jiangsu University , Zhenjiang , P.R. China and.
authors.forename: Ke-Ping
authors.initials: KP
authors.lastname: Chen
authors.affiliation: b Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P.R. China.
authors.forename: Cheng-gang
authors.initials: CG
authors.lastname: Huang
authors.affiliation: b Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P.R. China.
authors.forename: Guoyu
authors.initials: G
authors.lastname: Pan
mesh_terms: D000818:Animals; D001599:Berberine / Q000493:pharmacokinetics*; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000494:pharmacology; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: C000609070:Oatp1a1 protein, rat; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503597:Slco1a4 protein, rat; C421207:Slco1b2 protein, rat; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D001599:Berberine; D012293:Rifampin
keywords: Berberine; organic anion-transporting polypeptides; organic cation transporter; primary hepatocytes