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目的建立自由活动大鼠颈静脉血管微透析技术,比较大鼠在麻醉与清醒两种状态下丹参素药动学的差异。方法设计颈静脉微透析组件,包括颈静脉导管、导管固定装置、阻塞管及软微透析探针,可预先手术将导管插入实验动物颈静脉,另一端用导管固定装置固定在动物背部。另在下肢静脉处植入给药导管,一并在背部固定。手术恢复后,将微透析探针沿导管插入血管,在动物自由活动状态下进行血液微透析采样。10只SD大鼠分两组,每组5只,作颈静脉微透析预处理后,通过给药导管按40 mg.kg-1单剂量静注丹参素,分别在麻醉与清醒状态自由活动状态下进行血液微透析,应用HPLC紫外检测器测定透析液样品中丹参素浓度,绘制血药浓度-时间曲线,并计算药动学参数。结果成功获得清醒自由活动状态与麻醉状态下丹参素在大鼠体内的药-时曲线,计算得到大鼠在清醒与麻醉状态下丹参素药动学参数,分别为:AUC0-∞(3 517.3±7 754.5)、(10 739.8±2 458.8)mg.min.L-1;MRT0-∞(37.0±7.7)、(67.7±3.8)min;t1/2zeta(69.6±33.4)、(123.1±16.1)min;ρmax(290.0±90.3)、(256.4±15.5)mg.L-1;CLz(11.7±2.0)、(3.9±1.0)mL.min-1;Vssz(423.8±57.0)、(260.9±58.9)mL.kg-1。结论成功建立了自由活动大鼠颈静脉血管微透析技术。应用该技术对丹参素在清醒自由活动和麻醉大鼠体内药动学过程进行了比较研究,结果表明,两种状态下的药动参数有显著性差异。取血等强应激可能影响药动学过程,因此自由活动大鼠血液微透析技术有可能成为药动学研究的重要方法 。
OBJECTIVE: To establish a method of free micro-dialysis of jugular vein in rats and to compare the pharmacokinetics of Danshensu in anesthetized and awake rats. Methods The jugular vein microdialysis components, including the jugular vein catheter, catheter fixation device, occlusion tube and soft microdialysis probe, were designed. The catheter could be inserted into the jugular vein of experimental animals preoperatively and the other end fixed to the animal’s back with catheter fixing device. Another catheter in the lower extremity vein catheterization, together with the back fixed. After the operation was resumed, the microdialysis probe was inserted into the blood vessel along the catheter, and blood microdialysis sampling was performed while the animal was in a free state. Ten SD rats were divided into two groups with 5 rats in each group. After being pretreated with microdialysis in the jugular vein, Danshensu was intravenously administered by a single dose of 40 mg.kg-1 through the catheter, respectively. During free anesthesia and awake state, Under the condition of blood microdialysis, the concentration of Danshensu in the dialysate sample was determined by HPLC ultraviolet detector, and the blood concentration-time curve was drawn and the pharmacokinetic parameters were calculated. Results The pharmacokinetics parameters of Danshensu in awake and anesthetized rats were calculated and the pharmacokinetic parameters of Danshensu in conscious and free state under anesthesia were obtained. The AUC0-∞ (3 517.3 ± 7754.5), (10 739.8 ± 2 458.8) mg.min.L-1; MRT0-∞ (37.0 ± 7.7), (67.7 ± 3.8) min; t1 / 2zeta (69.6 ± 33.4), (123.1 ± 16.1) min ; Pmax (290.0 ± 90.3), (256.4 ± 15.5) mg.L-1; CLz (11.7 ± 2.0), (3.9 ± 1.0) mL.min-1; Vssz (423.8 ± 57.0) and (260.9 ± 58.9) mL .kg-1. Conclusion The successful establishment of free-living rat microvasculature of jugular vein. The application of the technology of danshensu in awake free and anesthetized rats in vivo pharmacokinetic process were compared, the results show that the two states pharmacokinetic parameters were significantly different. Blood and other strong stress may affect the pharmacokinetic process, so freely moving blood microdialysis technology may become an important method of pharmacokinetic studies.