摘要
目的采用Cocktail探针药物法评价威麦宁胶囊对大鼠体内6种CYP450亚型酶活性的影响。方法分别选用甲苯磺丁脲、氯唑沙宗、茶碱、咪达唑仑、奥美拉唑和右美沙芬作为CYP2C6、CYP2E1、CYP1A2、CYP3A2、CYP2D1和CYP2D2的探针底物。大鼠每日灌胃威麦宁胶囊1.6 g·kg-1,采用LC-MS/MS测定给药前后大鼠体内6种混合探针的血药浓度,计算药动学参数。结果威麦宁胶囊连续给药2周后,与给药前相比,奥美拉唑ρmax、AUC0-t、tmax及AUC0-∞显著升高(P<0.05);咪达唑仑ρmax、AUC0-t和AUC0-∞显著升高(P<0.01或P<0.05);右美沙芬ρmax、AUC0-t升高(P<0.05);甲苯磺丁脲t1/2、AUC0-∞和tmax显著升高(P<0.01或P<0.05),而CL/F显著降低(P<0.01),ρmax、AUC0-t无显著改变(P>0.05);氯唑沙宗ρmax升高(P<0.05),CL/F降低(P<0.05),AUC0-t升高但无显著差异(P>0.05);茶碱ρmax、AUC0-t升高但无显著差异(P>0.05)。表明奥美拉唑、咪达唑仑和右美沙芬代谢明显减慢(均P<0.05),茶碱、甲苯磺丁脲、氯唑沙宗的代谢无显著差异;威麦宁胶囊对大鼠体内CYP2D1、CYP3A2、CYP2D2酶有抑制作用,对CYP1A2、CYP2C6、CYP2E1酶的活性无显著影响。结论当威麦宁胶囊与CYP2C19、CYP3A4、CYP2D6酶的底物药物合用时,需要调整给药剂量,避免因药物相互作用使体内血药浓度过高产生毒副作用。
AIM To observe the influence of Weimaining capsule on activities of cytochrome P450 by Cocktail probe drugs in rats. METHODS Use tolbutamide, chlorzoxazone, theophylline, midazolam, omeprazole and dextromethorphan as the probe drugs of CYP2C6, CYP2E1, CYP1A2, CYP3A2, CYP2D1 and CYP2D2. The six probe drugs were simultaneously given to rats before and after Weimaining capsule （1.6 g·kg^-1） . The plasma concentrations of the six probe drugs were determined by LC- MS/MS and their corresponding pharmacokinetic parameters were calculated. RESULTS There were some differences between the six probe drugs in plasma concentrations and the corresponding pharmacokinetic parameters in rats after administration of Weimaining capsule for two weeks. Comparing with before, the pmax, AUC0-t, tmax arid AUC0-∞ of omeprazole increased （P 〈 0.05） . The p AUC0-t and AUC0-∞ of midazolam increased significantly （P 〈 0.05 or P 〈 0.01 ）. The pmax and AUC0-t of dextromethorphan increased （P 〈 0.05）. The t1/2, AUC0-∞ and tmax of tolbutamide increased significantly （P 〈 0.05 or P 〈 0.01 ）, but CL/F reduced significantly （P 〈 0.01 ）, although pmax and AUC0-t increased but no significantly difference （P 〉 0.05）. The chlorzoxazone＇ s pmax increased （P 〈 0.05）, but CL/F reduced （P 〈 0.05）, AUC0-t increased but no significantly difference （P 〉 0.05）. The theophylline＇ s pmax and AUC0-t increased but no significantly difference （P 〉 0.05）. So the metabolisms of omeprazole, midazolam and dextromethorphan reduced significantly （P 〈 0.05） , but no significantly difference in theophylline, tolbutamide and chlorzoxazone. It was indicated that Weimaining capsule could restrain CYP2D1, CYP3A2, CYP2D2 activity significantly, while had no significant influence on the activities of CYP1A2, CYP2C6, CYP2E1 in rats. CONCLUSION In clinical, when the substrate drugs of CYP2C19, CYP3A4 and CYP2D6 are used with Weimaining capsule, the given doses should be adjusted to avoid the toxic and side effect as drug interactions lead to blood drug concentrations are too high.
出处
《中国新药与临床杂志》
CAS
CSCD
北大核心
2014年第8期593-598,共6页
Chinese Journal of New Drugs and Clinical Remedies
基金
江苏省中医药领军人才项目(LJ200906)
江苏高校优势学科建设工程资助项目(2010)
中药新药临床评价研究技术平台(南京)建设(2012ZX09303009-002)
