Yang Hui-Lin, Li Ying, Chen Yi, Chen Si-Ying, Li Yue-Ting, Huang Yong, Zheng Lin, Huang Jing, Wang Yong-Lin, Gong Zi-Peng
Provincial Key Laboratory of Pharmaceutics in Guizhou Province, Engineering Research Center for the Development and Application of Ethnic Medicine and Traditional Chinese Medicine(Ministry of Education), School of Pharmaceutical Sciences,Guizhou Medical University Guiyang 550004, China.
Zhongguo Zhong Yao Za Zhi. 2022 Dec;47(23):6320-6332. doi: 10.19540/j.cnki.cjcmm.20220623.204.
The Cocktail probe drug method was used to evaluate the effect of Laportea bulbifera extract on the different subtypes of CYP450 enzyme activities in rats, and to provide references for its clinical rational drug use. The rats were randomly divided into a high-dose L. bulbifera group(0.45 g·kg(-1)·d(-1)) and a low-dose L. bulbifera group(0.09 g·kg(-1)·d(-1)). After continuous gavage for 7 and 14 days, the Cocktail probe mixing solution, including caffeine, midazolam, tolbutamide, omeprazole, metoprolol, and chlorzoxazone, was injected into the tail vein, and the blood sample was obtained from the tail vein at different time points. Ultra-high performance liquid chromatography-mass spectrometry(UPLC-MS) was established to determine the concentration of six probe drugs in rat plasma. DAS 2.0 was used to calculate its pharmacokinetic parameters, and the effect of L. bulbifera extract on CYP1 A2, CYP2 C9, CYP2 C19, CYP2 D6, CYP2 E1, and CYP3 A4 in rats was investigated. As compared with the blank control group, under the omeprazole index, the AUC_(0-t) and AUC_(0-∞) of the 7-day administration groups and the 14-day high-dose group were significantly decreased, and the CLz and Vz were significantly increased. Under the midazolam index, the AUC_(0-t) and AUC_(0-∞) of the 7-day low-dose group and the 14-day administration group were significantly decreased, and the CLz was significantly increased. In addition, the AUC_(0-∞) of the 7-day high-dose group was also significantly decreased. Under the index of metoprolol, the AUC_(0-t) and AUC_(0-∞) of each experimental group were decreased significantly, and the CLz and Vz of the 7-day low-dose group and the 14-day low-dose group were increased significantly. Under the caffeine index, the AUC_(0-t) and AUC_(0-∞) of the 7-day administration groups were increased significantly, the CLz was decreased significantly, and the t_(1/2 z) of the 14-day high-dose group was increased significantly. Under the chlorzoxazone index, the AUC_(0-t) and AUC_(0-∞) of the 7-day low-dose group were increased significantly, and the CLz was decreased significantly. Under the tolbutamide index, there was no statistical difference in the pharmacokinetic parameters. In conclusion, L. bulbifera extract induces the activities of CYP2 C19, CYP3 A4, and CYP2 D6, inhibits the activities of CYP1 A2 and CYP2 E1, and does not affect the activity of CYP2 C9.
采用鸡尾酒探针药物法评价苎麻根提取物对大鼠CYP450酶不同亚型活性的影响，为其临床合理用药提供参考。将大鼠随机分为苎麻根高剂量组（0.45 g·kg⁻¹·d⁻¹）和低剂量组（0.09 g·kg⁻¹·d⁻¹）。连续灌胃7天和14天后，尾静脉注射含咖啡因、咪达唑仑、甲苯磺丁脲、奥美拉唑、美托洛尔和氯唑沙宗的鸡尾酒探针混合液，并于不同时间点从尾静脉取血样。建立超高效液相色谱-质谱联用（UPLC-MS）法测定大鼠血浆中6种探针药物的浓度。采用DAS 2.0计算其药代动力学参数，考察苎麻根提取物对大鼠CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP2E1和CYP3A4的影响。与空白对照组比较，在奥美拉唑指标下，7天给药组和14天高剂量组的AUC₀₋ₜ和AUC₀₋∞显著降低，CLz和Vz显著升高。在咪达唑仑指标下，7天低剂量组和14天给药组的AUC₀₋ₜ和AUC₀₋∞显著降低，CLz显著升高。此外，7天高剂量组的AUC₀₋∞也显著降低。在美托洛尔指标下，各实验组的AUC₀₋ₜ和AUC₀₋∞均显著降低，7天低剂量组和14天低剂量组的CLz和Vz显著升高。在咖啡因指标下，7天给药组的AUC₀₋ₜ和AUC₀₋∞显著升高，CLz显著降低，14天高剂量组的t₁/₂z显著延长。在氯唑沙宗指标下，7天低剂量组的AUC₀₋ₜ和AUC₀₋∞显著升高，CLz显著降低。在甲苯磺丁脲指标下，药代动力学参数无统计学差异。综上所述，苎麻根提取物诱导CYP2C19、CYP3A4和CYP2D6的活性，抑制CYP1A2和CYP2E1的活性，不影响CYP2C9的活性。
