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

Influence of ceftriaxone on pharmacokinetics, anticoagulation and antithrombotic effects of phenolic acids from Danhong injection in rats

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C_(max)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C_(max)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t_(max)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B_2(TXB_2)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。

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.