药学学报, 2013, 48(8): 1307-1311
引用本文:
郑子华, 朱晓霞, 甘 慧, 顾若兰, 吴卓娜, 孟志云, 窦桂芳. 巴曲酶在比格犬体内的药代动力学及药效学研究[J]. 药学学报, 2013, 48(8): 1307-1311.
ZHENG Zi-hua,ZHU Xiao-xia,GAN Hui,GU Ruo-lan,WU Zhuona,MENG Zhi-yun,DOU Gui-fang. Pharmacodynamics and pharmacokinetics of batroxobin in Beagle dog[J]. Acta Pharmaceutica Sinica, 2013, 48(8): 1307-1311.

巴曲酶在比格犬体内的药代动力学及药效学研究
郑子华1, 2, 朱晓霞2, 甘 慧2, 顾若兰2, 吴卓娜2, 孟志云2, 窦桂芳2*
(1. 沈阳药科大学生命科学与生物制药学院, 辽宁 沈阳 110016; 2. 军事医学科学院野战输血研究所, 北京 100850)
摘要:

对巴曲酶在比格犬体内的药动学和药效学进行联合研究, 以阐明其关联性, 为临床合理用药提供依据。首先建立了酶联免疫吸附测定 (enzyme-linked immuno sorbent assay, ELISA) 方法测定比格犬血浆中巴曲酶的血药浓度。其次, 比格犬静脉滴注1.45.722.8 mg·kg−1 3个剂量巴曲酶后, 不同时间点采集血浆样本, ELISA方法检测血浆药物浓度, 分析血药浓度经时间变化并计算药代动力学参数。同时, 检测血浆样品的血凝 四项: 凝血酶原时间 (prothrombin time, PT)、凝血酶时间 (thrombin time, TT)、活化部分凝血酶时间 (activated partial thromboplastin time, APTT)、纤维蛋白原 (fibrinogen, Fib) D-二聚体 (D-dimmer, D-D) 的变化, 分析其  与血药浓度变化的相关性。比格犬单次静脉滴注巴曲酶后5.722.8 mg·kg−1剂量内在体内的的消除可能呈现线性药代动力学的特征, 1.45.722.8 mg·kg−13个剂量的t1/2 (2.27 ± 0.42)(10.65 ± 2.19) (11.01 ± 3.51) h; Cmax (11.9 ± 1.72)(54.53 ± 12.38) (172.14 ± 47.33) ng·mL−1; AUClast (29.38 ± 3.69)(148.43 ± 72.85) (599.22 ± 359.61) ng·h·mL−1给药后Fib含量明显下降, 48 h后基本恢复; 给药后血浆中PTTTAPTT明显延长, 48 h3个参数基本恢复正常; 静脉滴注巴曲酶后比格犬的血浆药物浓度与其血浆中D-二聚体的含量呈同 步变化, 二者有明显的相关性, D-二聚体的含量变化可作为巴曲酶溶栓药物治疗的监控指标。

关键词:   
Pharmacodynamics and pharmacokinetics of batroxobin in Beagle dog
Abstract:

Healthy Beagle dogs were administrated with batroxobin by intravenous infusion at high, medium and low doses.  The study of pharmacodynamics and pharmacokinetics was intended to clarify the relevance of them and provided strong evidence for clinical use of batroxobin.  The blood samples were collected after injection based on the time schedule and samples were tested by ELISA method to get the concentration of batroxobin.  At the same time, changes of prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), fibrinogen (Fib) and D-dimmer were tested.  The results showed that the concentration of D-D increased significantly after administration compared with that of before administration.  The main pharmacokinetic parameters were as follows: t1/2 were (2.27 ± 0.42) h, (10.65 ± 2.19) h and (11.01 ± 3.51) h; Cmax were (11.9 ± 1.72) ng·mL−1, (154.53 ± 12.38) ng·mL−1 and (172.14 ± 47.33) ng·mL−1; AUClast were (29.38 ± 3.69) ng·h·mL−1, (148.43 ± 72.85) ng·h·mL−1 and (599.22 ± 359.61) ng·h·mL−1.  The elimination of batroxobin was found to be in accord with linear kinetics characteristics.  The results of pharmacodynamics showed that D-dimmer level increased significantly after the administration of batroxobin, which was similar with the changes of batroxobin plasma concentration.  Simultaneously, Fib concentrations in Beagle dog blood decreased significantly after the iv administration of batroxobin, while recovered to base level after 48 hours.  PT, TT and APTT significantly became longer after administration, which returned to normal level after 48 hours.  Especially, the D-dimmer levels and the batroxobin concentration in plasma after intravenous infusion of the drug were synchronized in Beagle dogs.  Changes between PD/PK results had obvious correlation, and the D-dimmer levels in plasma can be one of the important monitoring indicators of batroxobin in thrombolytic medication.

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