title: Interaction of five anthraquinones from rhubarb with human organic anion transporter 1 (SLC22A6) and 3 (SLC22A8) and drug-drug interaction in rats.
abstract: BACKGROUND
  Rhubarb is a well-known traditional Chinese medicine and has been used in China for thousands of years. Anthraquinone derivatives including rhein, emodin, aloe-emodin, chrysophanol and physcion are the important components in rhubarb.
  
  
  METHODS
  Here we studied the interaction of five anthraquinone derivatives with human renal organic anion transporter 1 (hOAT1) and hOAT3 stably expressed in cells, and interaction of rhein or rhubarb extract (RE) with furosemide (FS, substrate of OATs) in rats.
  
  
  RESULTS
  Uptake of 6-carboxyl fluorescein via hOAT1 and fluorescein via hOAT3 were markedly inhibited by rhein, emodin and aloe-emodin, and slightly inhibited by chrysophanol and physcion. The estimated IC₅₀ values for rhein, emodin, aloe-emodin and probenecid (typical inhibitor of hOAT1 and hOAT3) were 0.23, 0.61, 2.29 and 18.34 μM for hOAT1, and 0.08, 1.22, 5.37 and 5.83 μM for hOAT3, respectively. Furthermore, the data from the cellular accumulation assay indicated that these five compounds were not substrates of hOAT1 or hOAT3. Pharmacokinetic interaction between rhein and FS in rats showed that area under the curve (AUC₀-t) for FS was increased by 65% when coadministrated with rhein. RE was also used to interact with FS in rats and results showed that AUC₀-t of FS was increased by 32% and by 52% when coadministrated with single-dose or multiple-dose of RE, respectively.
  
  
  CONCLUSIONS
  These findings suggested that five anthraquinones inhibited hOAT1 and hOAT3, but these compounds were not transported by hOAT1 or hOAT3. Furthermore, rhein or RE, might cause drug-drug interaction when coadministrated with substrates of OAT1 or OAT3 in vivo.
authors.affiliation: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Ma
authors.affiliation: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.
authors.forename: Haihong
authors.initials: H
authors.lastname: Hu
authors.affiliation: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.
authors.forename: Yahong
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.
authors.forename: Yicong
authors.initials: Y
authors.lastname: Bian
authors.affiliation: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.
authors.forename: Huidi
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. Electronic address: yuls@zju.edu.cn.
authors.forename: Lushan
authors.initials: L
authors.lastname: Yu
authors.affiliation: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. Electronic address: zengsu@zju.edu.cn.
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D004347:Drug Interactions; D005665:Furosemide / Q000097:blood / Q000493:pharmacokinetics*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D012250:Rheum
chemical_list: D000880:Anthraquinones; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D010936:Plant Extracts; C114338:organic anion transport protein 3; D005665:Furosemide
keywords: 6-Carboxyfluorescein (PubChem CID: 76806); Aloe-emodin (PubChem CID: 10207); Anthraquinone; Chrysophanol (PubChem CID: 10208); Emodin (PubChem CID: 3220); Fluorescein (PubChem CID: 16850); Furosemide (PubChem CID: 3440); Organic anion transporters; Physcion (PubChem CID: 10639); Probenecid (PubChem CID: 4911); Renal transport; Rhein (PubChem CID: 10168)