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

Abstract

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

CLC Number:

R965.2

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.

References

[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.