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First published on May 19, 2006; DOI: 10.1124/dmd.106.009779

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Received for publication February 10, 2006.
Revised May 15, 2006.
Accepted for publication May 16, 2006.

Pharmacokinetics and Metabolism of the Flavonoid Scutellarin in Humans after a Single Oral Administration

Xiaoyan Chen 1, Liang Cui 2, Xiaotao Duan 2, Bin Ma 2, Dafang Zhong 1*

1 Shanghai Institute of Materia Medica, Chinese Academy of Sciences 2 Shenyang Pharmaceutical University

* Address correspondence to: E-mail: zhongdf{at}china.com

Abstract

Abstract Scutellarin is widely used in treating various cardiovascular diseases. Few data are available regarding its metabolism and pharmacokinetics in humans. The objectives of this study were to develop methods to identify major metabolites of scutellarin in human urine and plasma, and determine simultaneously the parent drug and its major metabolites in human plasma for pharmacokinetic studies. Four metabolites were detected in urine samples by liquid chromatography coupled with electrospray multi-stage mass spectrometry, but only one of them was found in plasma. Its structure was confirmed as scutellarein 6-O-{beta}-D-glucuronide by MS, NMR and UV absorbance spectra. The plasma concentrations of scutellarin and the major metabolite were simultaneously determined using liquid chromatography-tandem mass spectrometry. After a single oral administration of 60 mg scutellarin to 20 healthy subjects, the plasma concentrations of scutellarin were very low and its plasma concentration-time curve was also anomalous. Plasma concentration of the major metabolite was comparatively high and the peak plasma concentration was 87.0 ± 29.1 ng/ml. The Tmax was late (7.85 ± 1.62 h) and part of individual pharmacokinetic profiles showed double peaks, which indicated scutellarin could be absorbed into the intestine after hydrolysis to its aglycone by bacterial enzymes. This was followed by reconjugation in the intestinal cell and/or liver with glucuronic acid catalyzed by the phase II enzyme, which showed regioselectivity and species difference. The regioselectivity of glucurono-conjugation for scutellarin might be of importance for pharmacological activity. Plasma concentration of iso-scutellarin can be used as a biomarker of scutellarin intake.


Key words: first-pass metabolism, glucuronidation, human pharmacokinetics, mass spectrometry, metabolite identification, metabolite kinetics


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