Side-by-side Chinese-English

香丹注射液对大鼠体内华法林抗凝作用的药效学和药代动力学影响

姜美婷1 张文龙1 孙志丹1 周洋旭1 陈佳玉1 刘高峰1

(1.哈尔滨医科大学附属第二医院药学部黑龙江省高校重点实验室, 黑龙江哈尔滨 150086)

【摘要】研究香丹注射液在大鼠体内对华法林抗凝作用的影响。将大鼠随机分组并给药,于设定的系列时间点取血。测定凝血指标PT(prothrombin time,凝血酶原时间)和APTT(activated partial thromboplastin time,活化部分凝血活酶时间)并计算INR(international normalized ratio,国际标准化比值)。采用UPLC-MS/MS技术测定华法林对映体血药浓度,用DAS 2.0软件计算药代动力学参数,进行统计学分析比较组间差异。单剂量华法林研究结果表明,香丹注射液本身对PT,APTT及INR均无影响,但与华法林联用后,可使PT和INR升高(P<0.01),对APTT无影响;两药联用后,S-华法林的Cmax,AUC0-t,AUC0-∞升高(P<0.01),t1/2延长(P<0.01),而R-华法林的药动学参数无显著变化。稳态华法林研究结果表明,两药合用后,PT和INR升高(P<0.05),S-华法林血药浓度升高(P<0.01),R-华法林血药浓度无显著变化。研究结果表明,香丹注射液本身对凝血指标无影响,但可通过减慢S-华法林代谢而增强华法林的抗凝作用。

【关键词】 香丹注射液;华法林;抗凝作用;药物相互作用;药效学;药代动力学;

【DOI】

【基金资助】 国家自然科学基金项目(81173659);

Effects of Xiangdan Injection on pharmacokinetics and pharmacodynamics of warfarin in rats in vivo

JIANG Mei-ting1 ZHANG Wen-long1 SUN Zhi-dan1 ZHOU Yang-xu1 CHEN Jia-yu1 LIU Gao-feng1

(1.Key Laboratory of University in Heilongjiang Province, Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China 150086)

【Abstract】This study aimed at exploring the effect of Xiangdan Injection on anticoagulation of warfarin in rats in vivo. Rats were randomly assigned into different groups and then administered. Subsequently, the blood samples were collected at a set series of time points for the measurement of prothrombin time (PT) and activated partial thromboplastin time (APTT) values, and the international normalized ratio (INR) was calculated. The plasma concentrations of warfarin enantiomers were determined by UPLC-MS/MS technology, and pharmacokinetic parameters were calculated by DAS 2.0 software. Statistical analysis was performed to compare differences between the groups. Single-dose study of warfarin showed that Xiangdan Injection alone had no effects on PT, APTT or INR. When Xiangdan Injection was co-administered with warfarin, PT and INR values increased (P < 0.01), while APTT was unaffected; after co-administration of the two drugs, Cmax, AUC0-t, and AUC0-∞ of S-warfarin increased (P < 0.01), and t1/2 prolonged (P < 0.01), while the pharmacokinetic parameters of R-warfarin changed insignificantly. Steady-state study of warfarin showed that after co-administration of the two drugs, the PT and INR values increased (P < 0.05), and the plasma concentration of S-warfarin increased (P < 0.01), while the plasma concentration of R-warfarin changed insignificantly. The results have suggested that Xiangdan Injection itself has no effect on coagulation index while can enhance the anticoagulation of warfarin by delaying the metabolism of S-warfarin.

【Keywords】 Xiangdan Injection; warfarin; anticoagulation; drug interactions; pharmacodynamics; pharmacokinetics;

【DOI】

【Funds】 National Natural Science Foundation of China (81173659);

Download this article
    References

    [1] MENG L, DING C Y, AN J, et al. Research progress in clinical treatment of oral anticoagulants [J]. Pharmaceutical Care and Research, 2019, 19 (3): 166 (in Chinese).

    [2] HIRSH J, FUSTER V, ANSELL J, et al. American heart association/American college of cardiology foundation guide to warfarin therapy [J]. J Am Coll Cardiol, 2003, 41 (9): 1633.

    [3] AAOM clinical practice statement: management of patients on warfarin therapy [J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2016, 122 (6): 702.

    [4] LI H G, FAN R, MA N, et al. Research progress on pharmacokinetics factors of warfarin [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22 (11): 1292 (in Chinese).

    [5] Cardiovascular Disease Branch of Chinese Medical Association, Cardiovascular and Cerebrovascular Disease Professional Committee of Gerontological Society of China. 华法林抗凝治疗的中国专家共识 [J]. Chinese Journal of Internal Medicine, 2013, 52 (1): 76 (in Chinese).

    [6] GAO T, YANG L J, SHENG X K, et al. Analysis of chemical constituents of Xiangdan Injection by HPLC-Q-TOF/MS and GC/MS [J]. Chinese Traditional Patent Medicine, 2019, 41 (2): 107 (in Chinese).

    [7] ZENG S N. Curative effect of Xiangdan Injection in treating coronary heart disease stenocardia and drug safety analysis [J]. Journal of China Prescription Drug, 2017, 15 (1): 4 (in Chinese).

    [8] LUO Y, ZHANG Y, ZHANG X Y. Clinical observation of treating the acute phase of NSTEMI with Shenfu Injection plus Xiangdan Injection [J]. Journal of Emergency in Traditional Chinese Medicine, 2009, 18 (4): 554 (in Chinese).

    [9] HU X, WEI F. 中药注射剂治疗常见心血管疾病的研究进展 [J]. Chinese Journal of Clinical Rational Drug Use, 2015, 8 (26): 172 (in Chinese).

    [10] XUE Q D, JU A X, WANG P, et al. Effects of Compound Danshen Injection on activity of different subtypes of cytochrome P450 in rats [J]. Chinese Journal of Experimental Traditional Medical Formulae, 2015, 21 (14): 71 (in Chinese).

    [11] XU S Y, BIAN R L, CHEN X. 药理实验方法学 [M]. 3rd Ed. Beijing: People’s Medical Publishing House, 2002: 202 (in Chinese).

    [12] FENG L Y, LIANG X L, LI T T, et al. Influence of Danhong Injection on anticoagulant effect of warfarin in rats in vivo [J]. China Pharmacist, 2016, 19 (1): 1 (in Chinese).

    [13] ZHANG C Y. PT、APTT、TT、Fg检测及临床应用 [J]. China Practical Medical, 2015, 10 (7): 108 (in Chinese).

    [14] XIE H J, FU H Y, ZHU C F, et al. Effects of Danshen Injection (Salvia miltiorrhiza) on pharmacodynamics and pharamcokinetics of warfarin in rats [J]. Herald of Medicine, 2009, 28 (1): 36 (in Chinese).

    [15] SUN J, LU Y, LI Y, et al. Influence of Shenxiong Glucose Injection on the activities of six CYP isozymes and metabolism of warfarin in rats assessed using probe cocktail and pharmacokinetic approaches [J]. Molecules, 2017, 22 (11): 7.

    [16] ZHU J P, ZHAO R. Influence factors for the pharmacodynamics of warfarin [J]. Clinical Medication Journal, 2009, 7 (3): 55 (in Chinese).

    [17] HAN J Y. Research progress of pharmacist-participated warfarin anticoagulation manage [J]. Chinese Journal of Modern Applied Pharmacy, 2018, 35 (8): 1269 (in Chinese).

This Article

ISSN:1001-5302

CN:11-2272/R

Vol 45, No. 19, Pages 4740-4745

October 2020

Downloads:3

Share
Article Outline

Abstract

  • 1 Materials
  • 2 Methods
  • 3 Results
  • 4 Discussion
  • References