Luteolin is mainly metabolized by phase II enzymes in animals and humans with glucuronidation and sulfation as the two known metabolic pathways. Although methylation of luteolin was reported previously, the structure of the methylated metabolites and the enzymes involved in the process have not been clarified. In our study, two methylated metabolites, M1 (chrysoeriol) and M2 (diosmetin), were identified in the urine after intravenous administration of luteolin to rats, and the data suggested that the methylation was mediated by catechol-O-methyltransferase (COMT). When luteolin was coadministered with a specific COMT inhibitor, entacapone, the formation of M1 and M2 was significantly reduced, whereas the plasma concentration of luteolin increased. Methylation of luteolin was also studied in vitro using rat tissue homogenates. The apparent kinetic parameters associated with the formation of M1 and M2 in vitro were estimated, and regioselectivity of methylation of luteolin was observed. In the in vitro experiment, there was a preference for the formation of M2 over M1. In contrast, accumulation of M1 was preferred in vivo in both rat plasma and urine after an intravenous dose of luteolin. In conclusion, COMT played a crucial role in the disposition of luteolin in rats. Our results indicated that the methylation pathway in rats was significantly reduced when luteolin was coadministered with a specific COMT inhibitor. Therefore, COMT-associated drug-drug interactions need be considered in the future in luteolin clinical trials because the plasma concentrations and related therapeutic effects may be altered in vivo in the presence of a COMT inhibitor.
Footnotes
The work was supported by the National Major Special Project for Science and Technology Development of the Ministry of Science and Technology of China [Grant 2009ZX09304-003]; and the Bureau of Zhejiang Traditional Chinese Medicine, China [Grant 2007ZA012].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.037333.
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ABBREVIATIONS:
- COMT
- catechol-O-methyltransferase
- HPLC
- high-performance liquid chromatography
- DAD
- diode array detector
- MS/MS
- tandem mass spectrometry
- MRT0–t
- mean residence time from 0 to t postdose
- AUC0–t
- area under the plasma concentration versus time curve from 0 to t postdose
- AUC0–∞
- area under the plasma concentration versus time curve from 0 to infinity.
- Received November 18, 2010.
- Accepted January 5, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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