目的探索模拟高原环境中大鼠芬太尼单次给药后药代动力学变化及其可能的影响因素。方法使用随机数字表法将36只体质量为(250±20)g的健康雌性SD大鼠(6~8周龄)分为模拟高原环境急性暴露组(A组)、慢性暴露组(S组)和对照组(C组),每组1...目的探索模拟高原环境中大鼠芬太尼单次给药后药代动力学变化及其可能的影响因素。方法使用随机数字表法将36只体质量为(250±20)g的健康雌性SD大鼠(6~8周龄)分为模拟高原环境急性暴露组(A组)、慢性暴露组(S组)和对照组(C组),每组12只。急性暴露组和慢性暴露组在低压舱中模拟5000 m海拔高度分别饲养3 d和30 d,对照组在舱外(海拔300 m)饲养。每组随机选取6只大鼠,通过股静脉单次给予芬太尼,在给药前及给药后1、2、4、8、15、30、60、120、180 min经股动脉采集血液,采用液相色谱串联质谱法(liquid chromatography tandem mass spectrometry,LC-MS/MS)检测芬太尼血药浓度,使用WinNonlin 8.2软件计算药代动力学特征参数;剩余6只大鼠通过超声检测门静脉的内径、峰值流速及血流量,并取肝组织进行CYP3A1蛋白含量检测。结果急性暴露组和慢性暴露组大鼠在60、120、180 min 3个时间点的血药浓度显著低于对照组(P=0.002,P<0.001,P=0.001)。与对照组比较,急性暴露组清除率(clearance rate,CL)增加54.06%(P=0.021),平均驻留时间(MRT_(last))缩短24.21%(P=0.033);慢性暴露组CL增加50.10%(P=0.041),血药浓度-时间曲线下面积(AUC_(0-t)、AUC_(0-∞))、MRT_(last)分别降低18.92%(P=0.039)、27.54%(P=0.018)、33.61%(P=0.004)。慢性暴露组门静脉内径和血流量较对照组分别增加10.87%(P=0.006)、42.50%(P=0.006)。急性暴露组CYP3A1蛋白含量较对照组升高28.74%(P=0.048)。结论模拟高原环境中大鼠芬太尼单次给药后清除速率较平原环境显著加快,该现象可能与模拟高原环境中大鼠肝脏血流量增加以及肝脏CYP3A1蛋白表达增加有关。展开更多
Clinical drug-drug interactions（DDIs） induced by CYP3A may reduce the exposure and pharmacological activity of CYP3A substrate.Up-regulation of CYP3A mRNA is often used to evaluate inductive effect of test compounds...Clinical drug-drug interactions（DDIs） induced by CYP3A may reduce the exposure and pharmacological activity of CYP3A substrate.Up-regulation of CYP3A mRNA is often used to evaluate inductive effect of test compounds on CYP3A. A quantitative real time PCR assay was developed and validated for the absolute quantification of CYP3A1 and CYP3A2 mRNA.Specific primers of CYP3A1,CYP3A2 and GAPDH（glyceraldehyde-3-phosphate dehydrogenase,as a house-keeping gene） were well designed.The relationship between threshold cycle（Ct） and logarithm of the concentrations of CYP3A1, CYP3A2 and GAPDH was linear ranged from 1 attomol/μL to 1×10~6 attomol/uL with great inter- and intra-assay reproducibility. This method was successfully applied to investigate the time courses of CYP3A1 and CYP3A2 mRNA induction in rat liver after 100 mg/kg dexamethasone（DEX） administration by intraperitoneal（i.p.） injection.The baseline levels of CYP3A1 and CYP3A2 mRNAs were 37.78 attomol/ug（total RNA） and 252.31 attomol/ug（total RNA）,respectively.CYP3A1 and CYP3A2 mRNA values increased gradually to their peak levels（19- and 8- fold vs.baseline） within 24 h and 42 h,respectively,and then returned to their baseline 60 h after DEX administration.展开更多
文摘目的探索模拟高原环境中大鼠芬太尼单次给药后药代动力学变化及其可能的影响因素。方法使用随机数字表法将36只体质量为(250±20)g的健康雌性SD大鼠(6~8周龄)分为模拟高原环境急性暴露组(A组)、慢性暴露组(S组)和对照组(C组),每组12只。急性暴露组和慢性暴露组在低压舱中模拟5000 m海拔高度分别饲养3 d和30 d,对照组在舱外(海拔300 m)饲养。每组随机选取6只大鼠,通过股静脉单次给予芬太尼,在给药前及给药后1、2、4、8、15、30、60、120、180 min经股动脉采集血液,采用液相色谱串联质谱法(liquid chromatography tandem mass spectrometry,LC-MS/MS)检测芬太尼血药浓度,使用WinNonlin 8.2软件计算药代动力学特征参数;剩余6只大鼠通过超声检测门静脉的内径、峰值流速及血流量,并取肝组织进行CYP3A1蛋白含量检测。结果急性暴露组和慢性暴露组大鼠在60、120、180 min 3个时间点的血药浓度显著低于对照组(P=0.002,P<0.001,P=0.001)。与对照组比较,急性暴露组清除率(clearance rate,CL)增加54.06%(P=0.021),平均驻留时间(MRT_(last))缩短24.21%(P=0.033);慢性暴露组CL增加50.10%(P=0.041),血药浓度-时间曲线下面积(AUC_(0-t)、AUC_(0-∞))、MRT_(last)分别降低18.92%(P=0.039)、27.54%(P=0.018)、33.61%(P=0.004)。慢性暴露组门静脉内径和血流量较对照组分别增加10.87%(P=0.006)、42.50%(P=0.006)。急性暴露组CYP3A1蛋白含量较对照组升高28.74%(P=0.048)。结论模拟高原环境中大鼠芬太尼单次给药后清除速率较平原环境显著加快,该现象可能与模拟高原环境中大鼠肝脏血流量增加以及肝脏CYP3A1蛋白表达增加有关。
基金National Integrity Innovational Technology Platform of New Drug and Development(Grant No.2009ZX09301- 010)
文摘Clinical drug-drug interactions（DDIs） induced by CYP3A may reduce the exposure and pharmacological activity of CYP3A substrate.Up-regulation of CYP3A mRNA is often used to evaluate inductive effect of test compounds on CYP3A. A quantitative real time PCR assay was developed and validated for the absolute quantification of CYP3A1 and CYP3A2 mRNA.Specific primers of CYP3A1,CYP3A2 and GAPDH（glyceraldehyde-3-phosphate dehydrogenase,as a house-keeping gene） were well designed.The relationship between threshold cycle（Ct） and logarithm of the concentrations of CYP3A1, CYP3A2 and GAPDH was linear ranged from 1 attomol/μL to 1×10~6 attomol/uL with great inter- and intra-assay reproducibility. This method was successfully applied to investigate the time courses of CYP3A1 and CYP3A2 mRNA induction in rat liver after 100 mg/kg dexamethasone（DEX） administration by intraperitoneal（i.p.） injection.The baseline levels of CYP3A1 and CYP3A2 mRNAs were 37.78 attomol/ug（total RNA） and 252.31 attomol/ug（total RNA）,respectively.CYP3A1 and CYP3A2 mRNA values increased gradually to their peak levels（19- and 8- fold vs.baseline） within 24 h and 42 h,respectively,and then returned to their baseline 60 h after DEX administration.
