Influence of Flavonoids from Galium verum L. on the activities of cytochrome P450 isozymes and pharmacokinetic and pharmacodynamic of warfarin in rats

Abstract

Background: Galium verum L., a traditional Chinese medicine, has been widely used in the folk in China. Preparations of G. verum L. were used to treat thromboembolic disease in clinic for many years and often combined with anticoagulants. Flavonoids from G. verum L. (FGVL) are the main active component. Materials and Methods: We assessed the potential influence of FGVL on the activities of five cytochrome P450 (CYP) enzymes and on the pharmacokinetic of warfarin in rats. The pharmacokinetics of five probe drugs and of warfarin was compared between control and FGVL-pretreated groups, which could estimate the effect on the activities of the five isozymes and warfarin metabolism. Moreover, the potential influence of FGVL on the pharmacodynamic of warfarin was investigated. Results: There was no significant difference in the pharmacokinetic parameters of chlorzoxazone and midazolam between control and FGVL-pretreated groups. However, the pharmacokinetic parameters of caffeine in every dose, metoprolol in middle dose, and tolbutamide in high dose were affected significantly (P < 0.05). It indicated that the metabolism of caffeine was markedly faster in FGVL-pretreated group but metoprolol in the middle dose and tolbutamide in the high-dose FGVL-pretreated group were markedly slower. The anticoagulation of combination group is better than warfarin group or FGVL group. This suggested that FGVL showed no effect on the enzyme activities of CYP2E1 and CYP3A2, induced the enzyme activities of CYP1A2, but inhibited the enzyme activities of CYP2D4 in the middle dose and CYP2C11 in high dose. Conclusion: This indicates that FGVL may increase the anticoagulation of warfarin in clinic dose. The dose of warfarin should be adjusted when combined with FGVL or preparations of G. verum L.