Abstract
Scutellarin or scutellarein-7-O-glucuronide (S-7-G) is a flavonoid used in the treatment of cardiovascular diseases. After oral administration to humans, S-7-G can hardly be detected, whereas its isomeric metabolite [scutellarein-6-O-glucuronide (S-6-G)] dominates in plasma. A preliminary study in rats also revealed a low bioavailability of S-7-G, as well as a high plasma concentration of S-6-G. Therefore, the present study tried to explore the possible causes of the unusual pharmacokinetics of scutellarin in humans through investigating the absorption and disposition of S-7-G in rats. After oral administration to rats, S-7-G was largely hydrolyzed in the intestinal tract and was absorbed as aglycone. While passing through the intestinal wall, aglycone was extensively glucuronidated into S-7-G and S-6-G (approximately 20:1), which subsequently entered the mesenteric blood (approximately 15:1). However, because S-7-G exhibited more rapid uptake in hepatocytes, was glucuronidated at a 2.7-fold higher rate in the liver, and was excreted in greater amounts through bile and urine than S-6-G, the S-7-G/S-6-G ratio eventually declined to approximately 1.5:1 in the systemic circulation. Findings revealed that S-7-G cannot be absorbed directly; S-7-G and S-6-G in the body were mostly generated from aglycone in the intestinal wall; a larger amount of S-7-G than S-6-G entered the mesenteric blood at the absorption stage, but the gap between them shrank quickly mainly because of the higher hepatic first-pass elimination of S-7-G. These findings in rats are of great value as reference for further study to accurately interpret the pharmacokinetics of S-7-G in humans.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.040550.
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ABBREVIATIONS:
- S-7-G
- scutellarin, scutellarein-7-O-glucuronide
- S-6-G
- isoscutellarin, scutellarein-6-O-glucuronide
- UDPGA
- uridinediphosphateglucuronic acid
- UGT
- UDP glucuronyltransferase
- RLM
- rat liver microsomes
- HBSS
- Hanks' balanced salt solution
- UPLC-Q/TOF MS
- ultraperformance liquid chromatography-quadrupole/time-of-flight mass spectrometry
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- AUC
- area under curve
- Papp
- apparent permeability
- MDF
- mass defect filter
- PBS
- phosphate-buffered saline
- HPLC
- high-performance liquid chromatography
- C/M ratio
- cell/medium concentration ratio
- CE
- collision energy
- S-6,7-diG
- 6,7-O-diglucuronide scutellarein
- MRT
- mean residence time.
- Received May 12, 2011.
- Accepted August 2, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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