阿司匹林与华法林在体肠吸收的相互作用研究

中国临床药理学与治疗学 ›› 2015, Vol. 20 ›› Issue (5): 486-492.

阿司匹林与华法林在体肠吸收的相互作用研究

李琳, 张炜, 沈陈林, 张平, 黄晓晖

安徽医科大学药学院,合肥 230032,安徽

收稿日期:2014-12-30 修回日期:2015-05-08 发布日期:2015-06-11
通讯作者: 黄晓晖,男,博士,教授,硕士生导师,研究方向:临床药理学和定量药理学。Tel: 13855183138 E-mail: mathdrug@sina.com
作者简介:李琳,女,硕士研究生,研究方向:定量药理学和临床药代动力学。Tel: 13721084770 E-mail: lilin-6821689@163.com
基金资助:
国家自然科学基金(81173133)

Study of drug interaction between aspirin and warfarin in situ intestinal absorption model

LI Lin, ZHANG WEI, SHEN Chen-lin, ZHANG Ping, HUANG Xiao-hui

School of Pharmacy,Anhui Medical University,Hefei 230032,Anhui,China

Received:2014-12-30 Revised:2015-05-08 Published:2015-06-11

摘要/Abstract

摘要： 目的: 考察阿司匹林与华法林联用肠吸收变化情况。方法: 建立大鼠在体分肠段单向肠灌流模型,应用重量法校正灌流液体积,并采用高效液相色谱法测定灌流液中阿司匹林、华法林对映体的浓度,分别计算其吸收速率常数(K_a)和表观吸收系数(P_app),定量比较单用组、联用组和诱导组中阿司匹林、S-和R-华法林的肠吸收差异。结果: 与单用华法林组相比,合用阿司匹林组中S-和R-华法林的吸收无明显变化(P＞0.05),阿司匹林诱导组中S-和R-华法林在十二指肠和空肠段的吸收显著降低(P＜0.05);与单用阿司匹林相比,合用华法林组和华法林诱导组中阿司匹林在各肠段的吸收均无明显变化(P＞0.05)。结论: 长期使用阿司匹林对华法林对映体在十二指肠和空肠段的吸收有抑制作用,且不存在立体选择性,而华法林对阿司匹林的吸收影响不明显。

关键词: 阿司匹林, S-华法林, R-华法林, 肠吸收, HPLC, 药物相互作用

Abstract: AIM: To evaluate the interaction between aspirin and warfarin on absorption in situ.METHODS: The rat single-pass intestinal perfusion model was performed to investigate the intestinal absorption of drugs, and gravimetry was used to correct the perfusion volume. The concentrations of aspirin, S- warfarin and R- warfarin in the perfusion samples were determined by HPLC. The absorption rate constants (K_a) and apparent permeability coefficients (P_app) were calculated to assess the differences between absorption of aspirin, S-warfarin and R-warfarin among the aspirin group, warfarin group, combination group, aspirin-induced and warfarin-induced groups.RESULTS: There were no significant differences in S-warfarin and R-warfarin absorption rates compared to warfarin combined with aspirin group(P＞0.05). The K_a and P_app of S-warfarin and R-warfarin in the duodenum and jejunum were significantly decreased in aspirin-induced group compared with that of warfarin-induced group(P＜0.05). No significant differences in aspirin absorption in the four intestinal segments were observed between aspirin group and aspirin combined with warfarin group or warfarin-induced group(P＞0.05).CONCLUSION: Prolonged use of aspirin can obviously decrease the absorption of S-and R-warfarin in the duodenum and jejunum,and there was no difference between the two enantiomers. The absorption rate of aspirin was not significantly affected by warfarin in this study.

Key words: aspirin, S- warfarin, R-warfarin, intestinal absorption, HPLC, drug interaction

中图分类号:

R965.2

李琳, 张炜, 沈陈林, 张平, 黄晓晖. 阿司匹林与华法林在体肠吸收的相互作用研究[J]. 中国临床药理学与治疗学, 2015, 20(5): 486-492.

LI Lin, ZHANG WEI, SHEN Chen-lin, ZHANG Ping, HUANG Xiao-hui. Study of drug interaction between aspirin and warfarin in situ intestinal absorption model[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(5): 486-492.

参考文献

[1] Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range[J]. Chest,1998,114(5 Suppl):445S-469S.
[2] Hennekens CH, Dalen JE.Aspirin in the primary prevention of cardiovascular disease: Current knowledge and future research needs[J]. Trends Cardiovasc Med,2014,24(8):360-366.
[3] Douketis JD.Combination warfarin-ASA therapy: Which patients should receive it, which patients should not, and why[J]. Thromb Res,2011,127(6):513-517.
[4] Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation[J].N Engl J Med, 2009,361(12):1139-1151.
[5] ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study[J].Am Heart J, 2010,159(3):340-347.
[6] Madhwal S, Lincoff AM, Rolston DD. Should patients on long-term warfarin take aspirin for heart disease[J]? Cleve Clin J Med,2008, 75(3):206-208.
[7] Dentali F, Douketis JD, Lim W, et al. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease[J].Arch Intern Med,2007,167(2):117-124.
[8] HUANG Xiao-hui,WANG Xia-qin,TANG Hai-qin,et al.Pharmacokinetic interaction between warfarin and aspirin in rats[J].Chin J Clin Pharmacol Ther,2012,17(6):189-195.
[9] Shen CL, Huang XH, Huang JH, et al.Development and validation of a RP-HPLC method for simultaneous determination of warfarin enantiomers,aspirin and salicylic acid in beagle plasma:application to pharmacokinetic study[J]. Lat Am J Pharm,2013,32(5):679-687.
[10]LIU Hui-chen.Advance in search for stereoselectivity in pharmacokinetics and its effect factors of chiral drugs[J]. Chin J Clin Pharmacol Ther,2003,19(5):380-383.
[11]Fagerholm U, Johansson M, Lennernas H. Comparison between permeability coefficients in rat and human jejunum[J]. Pharmaceut Res,1996,13(9):1336-1342.
[12]Sutton SC, Rinaldi MT, Vukovinsky KE. Comparison of the gravimetric,phenol red,and14C-PEG-3350 methods to determine water absorption in the rat single-pass intestinal perfusion model [J]. AAPS Pharm Sci,2001,3(3):93-97.
[13]ZENG S. Pharmacokinetics [M].Zhe jiang:Zhe jiang University Publishers, 2004: 1971.
[14]Chai GH, Hu FQ, Sun J, et al.Transport pathways of solid lipid nanoparticles across madin-darby canine kidney epithelial cell monolayer[J]. Mol Pharm,2014,11(10):3716-3726.
[15]Leschziner GD,Andrew T,Pirmohamed M, et al.ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research[J].Pharmacogenomics J, 2007,7(3):154-179.
[16]Sussman NL, WaltershiedM, Butler T, et al. The predictive nature of high-through put toxicity screening using a human hepatocyte cell line[J]. Cell Notes,2002, 3(5):7-10.
[17]Wadelius M, Sörlin K, Wallerman O, et al.Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors[J]. Pharmacogenomics J,2004,4(1):40-48.
[18]De Oliveira Almeida VC, De Souza Ferreira AC, Ribeiro DD,et al.Association of the C3435T polymorphism of theMDR1gene and therapeutic doses of warfarin in thrombophilic patients[J]. J Thromb Haemost,2011,9(10):2120-2122.
[19]Jung KH, Chu K, Lee ST, et al.Prolonged Use of Aspirin Alters Human and Rat Intestinal cells and thereby Limits the Absorption of clopidogrel[J]. Clin Pharmacol Ther, 2011, 90(4): 612- 619.