Abstract
Scutellarin [scutellarein-7-O-glucuronide (S-7-G)] displayed a unique pharmacokinetic profile in humans after oral administration: the original compound was hardly detected, whereas its isomeric metabolite isoscutellarin [scutellarein-6-O-glucuronide (S-6-G)] had a markedly high exposure. Previous rat study revealed that S-7-G and S-6-G in the blood mainly originated from their aglycone in enterocytes, and that the S-7-G/S-6-G ratio declined dramatically because of a higher hepatic elimination of S-7-G. In the present study, metabolite profiling in human excreta demonstrated that the major metabolic pathway for S-6-G and S-7-G was through further glucuronidation. To further understand the cause for the exposure difference between S-7-G and S-6-G in humans, studies were conducted to uncover mechanisms underlying their formation and elimination. In vitro metabolism study suggested that S-7-G was formed more easily but metabolized more slowly in human intestinal and hepatic microsomes. Efflux transporter study showed that S-6-G and S-7-G were good substrates of breast cancer resistance protein and multidrug resistance-associated protein (MRP) 2 and possible substrates of MRP3; however, there was no preference great enough to alter the S-7-G/S-6-G ratio in the blood. Among the major hepatic anion uptake transporters, organic anion-transporting polypeptide (OATP) 2B1 played a predominant role in the hepatic uptake of S-6-G and S-7-G and showed greater preference for S-7-G with higher affinity than S-6-G (Km values were 1.77 and 43.9 μM, respectively). Considering the low intrinsic permeability of S-6-G and S-7-G and the role of OATP2B1 in the hepatic clearance of such compounds, the selective hepatic uptake of S-7-G mediated by OATP2B1 is likely a key determinant for the much lower systemic exposure of S-7-G than S-6-G in humans.
Footnotes
This work was supported by the National Natural Science Foundation of China [Grants 30271525, 81173117].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- S-7-G
- scutellarin, scutellarein-7-O-glucuronide
- S-6-G
- isoscutellarin, scutellarein-6-O-glucuronide
- HPLC
- high-performance liquid chromatography
- HLM
- human liver microsomes
- HIM
- human intestinal microsomes
- RLM
- rat liver microsomes
- UGT
- UDP-glucuronosyltransferase
- MRP
- multidrug resistance-associated protein
- BCRP
- breast cancer resistance protein
- HBSS
- Hanks' balanced salt solution
- HEK
- human embryonic kidney
- OATP
- organic anion-transporting polypeptide
- OAT
- organic anion transporter
- RIM
- rat intestinal microsomes
- MDR
- multidrug resistance protein
- UPLC
- ultraperformance liquid chromatography
- TOF
- time of flight
- MS
- mass spectrometry
- LC-MS/MS
- liquid chromatography/tandem mass spectrometry
- E2-17β-G
- estradiol-17β-d-glucuronide
- CE
- collision energy
- S-6,7-diG
- scutellarein-6,7-diglucuronide
- GlcUA
- glucuronic acid.
- Received June 11, 2012.
- Accepted July 20, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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