Abstract
Some of the components found in herbs may be inhibitors or inducers of cytochrome P450 enzymes, which may therefore result in undesired herb-drug interactions. As a component extracted from Radix Scutellariae, the direct effect of baicalin on cytochrome P450 has not been investigated sufficiently. In this study, we investigated concentration-dependent inhibitory effect of baicalin on the plasma protein binding and metabolism of chlorzoxazone (CZN), a model CYP2E1 probe substrate, in rats in vitro and in vivo. Animal experiment was a randomized, three-period crossover design. Significant changes in pharmacokinetic parameters of CZN such as Cmax, t1/2 and Vd were observed after treatment with baicalin in vivo (P<0.05). Cmax decreased by 25% and 33%, whereas t1/2 increased by 34% and 53%, Vd increased by 37% and 50% in 225 mg/kg and 450 mg/kg baicalin-treated rats, respectively. The AUC and CL of CZN were not affected (P>0.05). Correlation analysis showed that the changes in CZN concentrations and baicalin concentrations were in good correlation (r>0.99). In vitro experiments, baicalin decreased the formation of 6-OH-chlorzoxazone in a concentration-dependent manner and exhibited a competitive inhibition in rat liver microsomes, with a Ki value of 145.8 µM. The values of Cmax/Ki were 20 and 39 after treatment with baicalin (225 and 450 mg/kg), respectively. Protein binding experiments in vivo showed that the plasma free-fraction (fu) of CZN increased 2.6-fold immediately after baicalin treatment (450 mg/kg) and in vitro showed that baicalin (125–2500 mg/L) increased the unbound CZN from 1.63% to 3.58%. The results indicate that pharmacokinetic changes in CZN are induced by inhibitory effect of baicalin on the plasma protein binding of CZN and CYP2E1 activity.
Highlights
Baicalin is a major flavone extracted from Radix Scutellariae, a plant which was widely used in traditional Chinese herbal medicine [1,2]
This clearly illustrated that the administration of baicalin to female Sprague-Dawley rats significantly altered the pharmacokinetics of CZN
The Cmax decreased by 25% and 33%, whereas t1/2 increased by 34% and 53%, Vd increased by 37% and 50% in different doses (225 and 450 mg/kg) of baicalin treated rats, respectively
Summary
Baicalin is a major flavone extracted from Radix Scutellariae, a plant which was widely used in traditional Chinese herbal medicine [1,2]. Baicalin has been used in a variety of preparations such as Huang-Lian-Jie-Du-Tang, SanHuang-Xie-Xin-Tang, Da-Chai-Hu-Tang, and Xiao-Chai-HuTang et al [4]. These herbal medicines have been used in Asia since ancient times and have been taken by European and American as remedy supplements and herbal teas in recent years [5,6]. Some of the components found in herbs may be inhibitors, inducers, or substrates of cytochrome P450 (CYP) enzymes, and may cause undesired herb-drug interactions, and potentially limit its clinic application. The effect of baicalin to different kinds of cytochrome P450 has not been completely understood and the direct relationship between baicalin and CYP2E1 is still unclear
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