A Quantitative Study Of Drug-drug Interaction Between Warfarin And Aspirin In Rats

Warfarin is the most widely used anticoagulant drug in clinical setting forprevention and treatment of atrial fibrillation. It has complex pharmacological effects,pharmacodynamic factors and narrow therapeutic range. The main complication is thebleeding risk. Aspirin is also used to treat thrombus in clinical practice. But if relying ona high dosage of aspirin to prevent thromboembolism, patients could suffer from vertigo,tinnitus and other gastrointestinal side effects. Recently more and more researchesdemonstrate that, this combination of these two drugs could reach a better anticoagulanteffect. This combination therapy can also be used for deep vein thrombosis, pulmonaryembolism, ventricular mural thrombus, atrial fibrillation and coronary coronary heartdisease in patients with atrial fibrillation. On the other hand, many studies have alsoshown that the combination therapy may greatly increase the bleeding risk. When andhow to conduct the warfarin plus aspirin conbined therapy is very controversial inclinical practice. However, the related preclinical study is rare.The aim of the present study is to explore pharmacokinetic and pharmacodynamicinteraction between warfarin and aspirin in rats. This study was divided into three parts:(1) The aim of part one was to establish a determination of content of aspirin and warfarin method which could provide a good basis for related researches and for clinicalmonitoring.(2) The aim of part two was to quantitatively study the effects of aspirin onthe pharmacokinetics and pharmacodynamics of warfarin in rats. The pharmacokineticand pharmacodynamic parameters were calculated and compared. The results show that,aspirin has limited effects on the pharmacokinetics but no effects on thepharmacodynamics of single dose warfarin in rats.(3) The aim of part three was toquantitatively study the dose optimization of drug-drug interaction of warfarin andaspirin in rats using weighted modification model and nonlinear mixed effect model.The results show that, if using platelet aggregation rate as the pharmacologic index, therole of aspirin is more important than that of warfarin when used combinedly. Theoptimal combination proportion between these two drugs was1:250(warfarin/aspirin)and the nature of interaction was additive when the indicator is platelet aggregation rate.