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European Journal of Drug Metabolism and Pharmacokinetics

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01-12-2017 | Original Research Article

Catechol-O-Methyltransferase and UDP-Glucuronosyltransferases in the Metabolism of Baicalein in Different Species

Authors: Ruiya Zhang, Yonglei Cui, Yan Wang, Xiangge Tian, Lu Zheng, HaiJian Cong, Bin Wu, Xiaokui Huo, Chao Wang, BaoJing Zhang, Xiaobo Wang, Zhonghui Yu

Published in: European Journal of Drug Metabolism and Pharmacokinetics | Issue 6/2017

Abstract

Background

Baicalein is the major bioactive flavonoid in some herb medicines and dietary plants; however, the detailed metabolism pathway of its major metabolite oroxylin A-7-O-β-d-glucuronide in human was not clear. It was important to illustrate the major metabolic enzymes that participate in its elimination for the clinic use of baicalein.

Objectives

We first revealed a two-step metabolism profile for baicalein and illustrated the combination of catechol-O-methyltransferase (COMT) and uridine diphosphate-glucuronosyltransferases (UGTs) in drug metabolism, further evaluated its bioactivity variation during drug metabolism.

Methods

The metabolism profiles were systematically characterized in different human biology preparations; after then, the anti-inflammatory activities of metabolites were evaluated in LPS-induced RAW264.7 cell.

Results

The first-step metabolite of baicalein was isolated and identified as oroxylin A; soluble-bound COMT (S-COMT) was the major enzyme responsible for its biotransformation. Specially, position 108 mutation of S-COMT significantly decreases the elimination. Meantime, oroxylin A was rapidly metabolized by UGTs, UGT1A1, -1A3, -1A6, -1A7, -1A8, -1A9, and -1A10 which were involved in the glucuronidation. Considerable species differences were observed with 1060-fold K _m (3.05 ± 1.86–3234 ± 475 μM) and 330-fold CL_int (5.93–1973 μL/min/mg) variations for baicalein metabolism. Finally, the middle metabolite oroxylin A exhibited a potent anti-inflammatory activity with the IC₅₀ value of 28 μM.

Conclusion

The detailed kinetic parameters indicated that COMT provide convenience for the next glucuronidation; monkey would be a preferred animal model for the preclinical investigation of baicalein. Importantly, oroxylin A should be reconsidered in evaluating baicalein efficacy against inflammatory diseases.

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Title: Catechol-O-Methyltransferase and UDP-Glucuronosyltransferases in the Metabolism of Baicalein in Different Species
Authors: Ruiya Zhang
Yonglei Cui
Yan Wang
Xiangge Tian
Lu Zheng
HaiJian Cong
Bin Wu
Xiaokui Huo
Chao Wang
BaoJing Zhang
Xiaobo Wang
Zhonghui Yu
Publication date: 01-12-2017
Publisher: Springer International Publishing
Published in: European Journal of Drug Metabolism and Pharmacokinetics / Issue 6/2017
Print ISSN: 0378-7966
Electronic ISSN: 2107-0180
DOI: https://doi.org/10.1007/s13318-017-0419-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Catechol-O-Methyltransferase and UDP-Glucuronosyltransferases in the Metabolism of Baicalein in Different Species

Abstract

Background

Objectives

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Objectives

Methods

Results

Conclusion

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