Effects of the total flavonoid extracts and the monomers of Daphne genkwa on CYP2C8 activity

This study aimed to assess the effects of total flavonoid extracts (TFDG) and the monomers of Daphne genkwa on the CYP2C8 activity in vitro and in vivo.The 50% inhibitory concentration (IC₅₀) values were used to determine the inhibitory effect of TFDG and its four monomers for the CYP2C8 activity by recombinant human CYP2C8 (RHCYP2C8) yeast microsome system in vitro, and the volume per dose index (VDI) was predicted the potential inhibition in vivo. The effects of multiple-dose administration of TFDG on the pharmacokinetic parameters of rosiglitazone in rats were evaluated.The IC₅₀ values of apigenin, luteolin, hydroxy-genkwanin, genkwanin, and TFDG were 7.27 μmol/L, 11.9 μmol/L, 28.1 μmol/L, 127 μmol/L, and 13.4 μg/mL, respectively. The VDI values of apigenin and TFDG were 2.15 L and 6.60 L. In vivo study, compared with the control group, the elimination phase half-life and mean residence time in the TFDG treatment group were significantly increased by 96.9% and 106.8% (<i>p &lt;</i>.05), respectively.Apigenin showed a moderate inhibitory effect on the CYP2C8 activity in vitro, while the other three monomers were weak inhibitors. TFDG had a strong inhibitory effect on CYP2C8 in vitro and in vivo, and also inhibited the metabolism of rosiglitazone in rats. This study aimed to assess the effects of total flavonoid extracts (TFDG) and the monomers of Daphne genkwa on the CYP2C8 activity in vitro and in vivo. The 50% inhibitory concentration (IC₅₀) values were used to determine the inhibitory effect of TFDG and its four monomers for the CYP2C8 activity by recombinant human CYP2C8 (RHCYP2C8) yeast microsome system in vitro, and the volume per dose index (VDI) was predicted the potential inhibition in vivo. The effects of multiple-dose administration of TFDG on the pharmacokinetic parameters of rosiglitazone in rats were evaluated. The IC₅₀ values of apigenin, luteolin, hydroxy-genkwanin, genkwanin, and TFDG were 7.27 μmol/L, 11.9 μmol/L, 28.1 μmol/L, 127 μmol/L, and 13.4 μg/mL, respectively. The VDI values of apigenin and TFDG were 2.15 L and 6.60 L. In vivo study, compared with the control group, the elimination phase half-life and mean residence time in the TFDG treatment group were significantly increased by 96.9% and 106.8% (<i>p &lt;</i>.05), respectively. Apigenin showed a moderate inhibitory effect on the CYP2C8 activity in vitro, while the other three monomers were weak inhibitors. TFDG had a strong inhibitory effect on CYP2C8 in vitro and in vivo, and also inhibited the metabolism of rosiglitazone in rats.

本研究旨在评估芫花总黄酮提取物（TFDG）及其单体成分对细胞色素P450 2C8（CYP2C8）活性的体外（in vitro）与体内（in vivo）影响。采用重组人CYP2C8（RHCYP2C8）酵母微粒体系统，通过半数抑制浓度（IC₅₀）值评定TFDG及其4种单体对CYP2C8活性的体外抑制效果；同时采用每剂量体积指数（VDI）预测其体内潜在抑制作用。本研究还评价了多次给药TFDG对大鼠体内罗格列酮（rosiglitazone）药代动力学参数的影响。芹菜素（apigenin）、木犀草素（luteolin）、羟基芫花素（hydroxy-genkwanin）、芫花素（genkwanin）及TFDG的IC₅₀值分别为7.27 μmol/L、11.9 μmol/L、28.1 μmol/L、127 μmol/L及13.4 μg/mL。芹菜素与TFDG的VDI值分别为2.15 L与6.60 L。体内研究结果显示，与对照组相比，TFDG给药组的消除相半衰期与平均驻留时间分别显著升高96.9%与106.8%（P < 0.05）。芹菜素对CYP2C8活性具有中等强度的体外抑制作用，其余3种单体仅表现出弱抑制活性。TFDG在体外与体内均对CYP2C8具有较强的抑制作用，同时可抑制大鼠体内罗格列酮的代谢。本研究旨在评估芫花总黄酮提取物（TFDG）及其单体成分对细胞色素P450 2C8（CYP2C8）活性的体外（in vitro）与体内（in vivo）影响。采用重组人CYP2C8（RHCYP2C8）酵母微粒体系统，通过半数抑制浓度（IC₅₀）值评定TFDG及其4种单体对CYP2C8活性的体外抑制效果；同时采用每剂量体积指数（VDI）预测其体内潜在抑制作用。本研究还评价了多次给药TFDG对大鼠体内罗格列酮（rosiglitazone）药代动力学参数的影响。芹菜素（apigenin）、木犀草素（luteolin）、羟基芫花素（hydroxy-genkwanin）、芫花素（genkwanin）及TFDG的IC₅₀值分别为7.27 μmol/L、11.9 μmol/L、28.1 μmol/L、127 μmol/L及13.4 μg/mL。芹菜素与TFDG的VDI值分别为2.15 L与6.60 L。体内研究结果显示，与对照组相比，TFDG给药组的消除相半衰期与平均驻留时间分别显著升高96.9%与106.8%（P < 0.05）。芹菜素对CYP2C8活性具有中等强度的体外抑制作用，其余3种单体仅表现出弱抑制活性。TFDG在体外与体内均对CYP2C8具有较强的抑制作用，同时可抑制大鼠体内罗格列酮的代谢。