A Metabolism-Based Synergy for Total Coumarin Extract of Radix and Ligustrazine on Migraine Treatment in Rats

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2018 Apr 26

PMID 29693578

Citations 9

Authors

Shan Feng

Xin He

Peiru Zhong

Jinyi Zhao

Cong Huang

Zhuohan Hu

Affiliations

Soon will be listed here.

Abstract

Radix , containing coumarins, which might affect cytochrome P450 enzyme (CYP450) activity, has been co-administered with ligustrazine, a substrate of CYP450s, for the clinical treatment of migraine. However, whether a pharmacokinetic-based synergy exists between Radix and ligustrazine is still unknown. In this study, the total coumarin extract (TCE) of Radix (50 mg/kg, orally) reinforced the anti-migraine activity of ligustrazine by declining head scratching, plasma calcitonin gene-related peptide, and serum nitric oxide, as well as increasing plasma endothelin levels in rats ( < 0.05). Moreover, the pharmacokinetic study reflected that TCE potentiated the area under the concentration⁻time curve of ligustrazine and prolonged its mean retention time in rats ( < 0.05). Besides, the IC for TCE, imperatorin and isoimperatorin inhibiting ligustrazine metabolism were 5.0 ± 1.02, 1.35 ± 0.46, 4.81 ± 1.14 µg/mL in human liver microsomes, and 13.69 ± 1.11, 1.19 ± 1.09, 1.69 ± 1.17 µg/mL in rat liver microsomes, respectively. Moreover, imperatorin and isoimperatorin were CYP450s inhibitors with IC < 10 µM for CYP1A2, 2C9, 2D6, and 3A4. Therefore, this study concluded that Radix could increase ligustrazine plasma concentration and then reinforce its pharmacological effect by inhibiting its metabolism through interference with CYP450s. This could be one mechanism for the synergy between Radix and ligustrazine on migraine treatment.

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