药学学报, 2019, 54(4): 701-709
引用本文:
张倩, 居文政, 郭建明, 李建萍, 姚毅, 唐志书, 赵步长, 段金廒. 头孢曲松改变丹红注射液酚酸类成分在大鼠体内药动学行为和抗凝血抗血栓药效的研究[J]. 药学学报, 2019, 54(4): 701-709.
ZHANG Qian, JU Wen-zheng, GUO Jian-ming, LI Jian-ping, YAO Yi, TANG Zhi-shu, ZHAO Bu-chang, DUAN Jin-ao. Influence of ceftriaxone on pharmacokinetics, anticoagulation and antithrombotic effects of phenolic acids from Danhong injection in rats[J]. Acta Pharmaceutica Sinica, 2019, 54(4): 701-709.

头孢曲松改变丹红注射液酚酸类成分在大鼠体内药动学行为和抗凝血抗血栓药效的研究
张倩1,2, 居文政2, 郭建明1, 李建萍1, 姚毅2, 唐志书3, 赵步长4, 段金廒1
1. 南京中医药大学, 江苏省中药资源产业化过程协同创新中心, 江苏省方剂高技术研究重点实验室, 江苏 南京 210046;
2. 南京中医药大学附属医院, 江苏 南京 210029;
3. 陕西中医药大学, 陕西 咸阳 712000;
4. 步长制药有限公司, 陕西 西安 710000
摘要:
基于临床数据挖掘结论,选取常见的丹红注射液与头孢曲松钠联合用药方案,设计实验考察在雄性成年Sprague-Dawley(SD)大鼠体内,连续7天尾静脉给予丹红注射液后,继续联合使用头孢曲松钠7天,对丹红注射液中的酚酸类成分p-香豆酸、丹酚酸D、迷迭香酸和丹酚酸B的药动学行为,以及抗血栓、抗凝血和抗血小板药效的影响。运用UHPLC-TQ-MS测定血药浓度后,用DAS 3.2.8计算丹红注射液中酚酸类成分在丹红注射液单用药组与联合用药组的药动学参数,并比较两组在90%置信区间最高血药浓度Cmax和药时曲线下面积AUC0-t的生物等效性。结果显示:与单用药组相比,联合用药组的p-香豆酸、丹酚酸D、迷迭香酸和丹酚酸B的Cmax不等效;丹酚酸D、迷迭香酸和丹酚酸B的AUC0-t不等效,而各成分的tmax没有显著性差异(P>0.05)。体内抗凝血实验结果显示:与单用药组比较,联合用药组的国际化标准比值(INR)显著升高(P<0.01),凝血酶原时间(PT)、凝血酶时间(TT)、活化部分凝血活酶时间(APTT)显著增加(P<0.05或P<0.01),而纤维蛋白原(FIB)值没有显著差异;抗血栓结果显示大鼠体内血清血栓烷素B2(TXB2)水平在联合用药组内极显著降低(P<0.01);而抗血小板结果没有显著性差异。综上结果表明:头孢曲松钠可能通过改变丹红注射液中的酚酸类成分在大鼠体内的药动学和药效学,增强丹红注射液的抗凝血和抗血栓作用。以上动物实验均通过南京中医药大学动物伦理审查。
关键词:    丹红注射液      头孢曲松钠      中西药相互作用      药动学      抗血栓      抗凝血      抗血小板     
Influence of ceftriaxone on pharmacokinetics, anticoagulation and antithrombotic effects of phenolic acids from Danhong injection in rats
ZHANG Qian1,2, JU Wen-zheng2, GUO Jian-ming1, LI Jian-ping1, YAO Yi2, TANG Zhi-shu3, ZHAO Bu-chang4, DUAN Jin-ao1
1. Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources, Nanjing University of Chinese Medicine, Nanjing 210046, China;
2. The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China;
3. Shaanxi University of Traditional Chinese Medicine, Xianyang 712000, China;
4. Buchang Pharma, Xi'an 710000, China
Abstract:
Danhong injection (DHI) and ceftriaxone sodium were used in combination based on their experimental uses in clinic. This study was designed to investigate the impact of ceftriaxone on pharmacokinetics and pharmacodynamics of the phenolic acids from DHI. After administration of DHI for 7 d, ceftriaxone (CFTX) was combined with DHI for the next 7 d in adult male Sprague-Dawley (SD) rats. All the drugs were administered through caudal vein. UHPLC-TQ-MS was applied in determining the plasma concentration of p-coumaric acid (p-CA), salvianolic acid D (SaD), rosmarinic acid (RA) and salvianolic acid B (SaB). The pharmacokinetic parameters of the combination group or the Danhong injection alone group were calculated by statistical moment method, Cmax and the average of the area under the curve AUC0-t using 90% confidence interval of the bioequivalence and bioavailability degree module in DAS 3.2.8 statistic software. The results showed that Cmax of p-CA, SaD, RA and SaB were unqualified within 90% confidence intervals for bioequivalence statistics. And the results showed that AUC0-t of SaD, RA and SaB within 90% confidence intervals for bioequivalence statistics were unqualified. There were no significant difference in the tmax (P>0.05). The results of anticoagulation in vivo showed that the international normalized ratio (INR), prothrombin time (PT), thrombin time (TT) and activated partial thromboplastin time (APTT) were significantly increased when combined with CFTX (P<0.05 or P<0.01). The results in antithrombotic effects revealed that the thromboxane B2 (TXB2) level in serum was significantly decreased (P<0.01) in the combination group compared with Danhong injection alone. However, there was no significant difference in antiplatelet effects. These results suggest that CFTX may enhance the anticoagulation and antithrombotic effects of DHI through altering pharmacokinetics and pharmacodynamics in SD rats.
Key words:    Danhong injection    ceftriaxone sodium    herb-drug interaction    pharmacokinetics    antithrombotic effect    anticoagulation    antiplatelet   
收稿日期: 2018-10-30
DOI: 10.16438/j.0513-4870.2018-0984
基金项目: 国家重点基础研究发展计划(973计划)资助项目(2011CB505300,2011CB505303);国家科技重大专项资助项目(2015ZX09501004001006);国家自然科学基金青年科学基金资助项目(81803795);江苏省中医药管理局科技项目(YB2017018);江苏省自然科学基金面上项目(BK20181504);江苏省自然科学基金青年科学基金项目(BK20180823).
通讯作者: 段金廒
Email: dja@njucm.edu.cn
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