title: Concentration-dependent inhibitory effect of Baicalin on the plasma protein binding and metabolism of chlorzoxazone, a CYP2E1 probe substrate, in rats in vitro and in vivo.
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 C(max), t(1/2) and V(d) were observed after treatment with baicalin in vivo (P<0.05). C(max) decreased by 25% and 33%, whereas t(1/2) increased by 34% and 53%, V(d) 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 C(max)/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.
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Gao
authors.forename: Dan
authors.initials: D
authors.lastname: Zou
authors.forename: Hai-Ling
authors.initials: HL
authors.lastname: Qiao
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002753:Chlorzoxazone / Q000494:pharmacology*; D018592:Cross-Over Studies; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D011485:Protein Binding; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D010936:Plant Extracts; C038044:baicalin; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone