Study The Effects And Molecular Mechanism Of Hawthorn Flavonoids On The Metabolism Of Ticagrelol In Rats

Background and pourpose:Acute coronary syndrome?ACS?is a serious cardiovascular disease,which seriously threats the human health,the main cause of this disease is the rupture of atherosclerotic plaques and leads to the exposure of tissue factor and collagen,which in turn causes platelet activation and aggregation,ultimately,it forms the thrombus.The first line of clinical prevention and treatment drugs are anticoagulant drugs.Ticagrelor,a novel cyclopentyltriazolyl oral antiplatelet drug,can rapidly and reversibly act on the adenosine diphosphate-mediated P2Y12 receptor,which significantly inhibitas platelet aggregation induced by adenosine diphosphate.In vivo,ticagrelor is mainly metabolized by CYP3A4,and its metabolite AR-C124910XX also has the same activity.Hawthorn,a kind of medicine and food homologous plant,it is mainly used to treat cardiovascular and cerebrovascular diseases and digestive system diseases in traditional medicine.It has many pharmacological effects such as lowering blood lipids,antioxidation,inhibiting inflammatory factors,and preventing platelet aggregation.The active ingredient is hawthorn flavonoids.Based on the preliminary study of the pharmacological effects of hawthorn flavonoids on reducing blood lipids,this study investigated the effect of hawthorn flavonoids on the metabolic kinetics of ticagrelor and its mechanism,in order to provide a theoretical basis for the clinical use of ticagrelor safely and combination therapy.Methods:In this study,SD male rats were used as experimental animals,which were randomly divided into 5 groups?T,TH,TM,TE,THME?and administered:T group:ticagrelor?18.0 mg/kg?;TH group:quercetin?0.7 mg/kg?in combination with ticagrelor?18.0 mg/kg?;TM group:luteolin?1.3 mg/kg?in combination with ticagrelor?18.0 mg/kg?;TE group:catechins?0.5 mg/kg?in combination with ticagrelor?18.0 mg/kg?;THME group:quercetin?0.7 mg/kg?,luteolin?1.3 mg/kg?,and catechin?0.5 mg/kg?in combination with ticagrelor?18.0 mg/kg?.?1?Blood samples were collected at 0,0.25,0.5,1.0,1.5,2.0,4.0,6.0,8.0,10.0,12.0,24.0,30.0,36.0 h,UPLC-MS/MS method was used to determin the concentration of ticagrelor in plasma samples.PKSolver pharmacokinetic software was used to process datas.The pharmacokinetic parameters of each group of rats were automatically fitted and calculated,and blood concentration-time curves were plotted.?2?Urine samples were collected at 0⁶.0,6.0⁸.0,8.0¹2.0,12.0²4.0 h,plasma samples were collected at 4.0,6.0,8.0,12.0,24.0 h,processed and assayed to study the effect of hawthorn flavonoids on the active metabolites of ticagrelor.?3?Plasma and urine samples were collected after 7d administration and processed for analysis.Metabolomics and multivariate statistical analysis were used to comprehensively evaluate the effects of hawthorn flavonoids in combination with ticagrelor on endogenous metabolites and metabolic pathways.Results:?1?The pharmacokinetics results showed that the C_max and AUC _0-36-36 of ticagrelor in the T group were 325.28±45.20 ng/mL and 3896.30±1140 ng/mL·h,respectively;the C_max and AUC _0-36-36 of ticagrelor in the TH group were 488.13±5.58 ng/mL and7330.94±505.30 ng/mL·h,increased 50.06%and 88.15%?P<0.05?,respectively;the Cmax of ticagrelor in the TM group was 396.78±63.79 ng/mL,increased 21.98%?P>0.05?,and AUC _0-36 was 5474.22±670.42 ng/mL·h,increased 40.50%?P<0.05?;the C_max of ticagrelor in the TE group was 293.13±84.86 ng/mL,decreased 9.88%?P>0.05?,and AUC 0-36 was 4241.71±943.50 ng/mL·h,increased 8.17%?P>0.05?;the C_max and AUC _0-36 of ticagrelor in the THME group were 487.63±4.88 ng/mL and8241.05±339.19 ng/mL·h,increased 49.92%and 111.51%76.04%?P<0.05?.?2?The results of hawthorn flavonoids on the active metabolites of ticagrelor showed that the combined use of flavonoids can reduce the content of active metabolites of ticagrelor in plasma samples and increase its content in urine samples.?3?The mechanism of hawthorn flavonoids on the metabolism of ticagrelor showed that hawthorn flavonoids were mainly through sphingolipid metabolism,arachidonic acid metabolism,valine,leucine and isoleucine biosynthesis;nicotinate and nicotinamide metabolism,ascorbate and aldarate metabolism metabolic pathways,etc.Conclusions:?1?Hawthorn flavonoids quercetin,luteolin,catechin,and mixed flavonoids had a certain influence on the pharmacokinetics of ticagrelor when used in combination with ticagrelor,when ticagrelor and hawthorn flavonoids were used in combination,hawthorn flavonoids can enhance the role of ticagrelor.?2?Metabolomics method were used to analysis the mechanism of quercetin,luteolin,catechins and mixed flavonoids on the metabolism of ticagrelor.It was found that hawthorn flavonoids affect the metabolism of ticagrelor mainly through lipids metabolism,arachidonic acid metabolism;valine,leucine and isoleucine biosynthesis,etc.