Department of Pharmacology, College of Basic Medicine, Tianjin Medical University , No. 22 Qixiangtai Road, Tianjin , P.R. China.
Drug Dev Ind Pharm. 2014 Feb;40(2):157-62. doi: 10.3109/03639045.2012.752499. Epub 2013 Jan 23.
To evaluate the effects of ischemia and reperfusion (IR) and ischemic preconditioning (IPC) on the metabolic activities of cytochrome P450 (CYP) isozymes in rats by a five-drug cocktail approach.
Cocktail approach was used to evaluate the influence of IR and IPC on the activities of CYP1A2, CYP2C9, CYP2E1, CYP2D6 and CYP3A4, which were reflected by the changes of pharmacokinetic parameters of five specific probe drugs: caffeine, chlorzoxazone, tolbutamide, metoprolol and midazolam, respectively. Rats were randomly divided into IR, IPC and sham groups, and then injected the mixture of five probe drugs. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by a HPLC method with UV detection. The pharmacokinetic parameters were calculated by the software of DAS 2.0.
The parameters including t(1/2β), CLs, AUC, MRT and K10 exhibited a similar tendency for both IR and IPC groups. Compared with sham group, CLs and K10 of five probe drugs were significantly lower (p < 0.05), AUC and t(1/2β) of five or some probe drugs were significantly increased in IR and IPC groups (p < 0.05). Compared with IPC group, CLs of five probe drugs were decreased and AUC were significantly increased in the IR group (p < 0.05).
IR can variably decrease the activities of CYP isozymes in rats and this decrease can be attenuated by IPC.
采用五药物鸡尾酒法评估缺血再灌注（IR）和缺血预处理（IPC）对大鼠细胞色素 P450（CYP）同工酶代谢活性的影响。
采用鸡尾酒法评估 IR 和 IPC 对 CYP1A2、CYP2C9、CYP2E1、CYP2D6 和 CYP3A4 活性的影响，这反映在五个特定探针药物的药代动力学参数变化上：咖啡因、氯唑沙宗、甲苯磺丁脲、美托洛尔和咪达唑仑。大鼠随机分为 IR、IPC 和假手术组，然后注射五种探针药物混合物。在一系列时间点采集血样，采用 HPLC-UV 法测定血浆中探针药物的浓度。使用 DAS 2.0 软件计算药代动力学参数。
IR 和 IPC 组的 t(1/2β)、CLs、AUC、MRT 和 K10 参数均呈现相似的趋势。与假手术组相比，IR 和 IPC 组的五种探针药物 CLs 和 K10 明显降低（p<0.05），五种或部分探针药物的 AUC 和 t(1/2β)明显增加（p<0.05）。与 IPC 组相比，IR 组五种探针药物的 CLs 降低，AUC 明显增加（p<0.05）。
IR 可不同程度地降低大鼠 CYP 同工酶的活性，IPC 可减轻这种降低。
