In Vitro Metabolism And Metabolic Interactions Between Ticagrelor And Stains

Objective:To study the in vitro metabolism of ticagrelor and investigate the drug-drug interactions between ticagrelor and some commonly used stains?simvastain,lovastain and atorvastain?,expecting to provide some useful information for the rational use of ticagrelor in clinic.Method:The metabolic reaction of ticagrelor was performed in rat liver microsomes.After incubation for a given time,the reaction was stopped with methanol containing an internal standard(diazepam,10 ng·mL^-1),and the protein was precipitated and centrifuged at 15,000 rpm.After the min,the supernatant was taken for analysis.The concentration of the active metabolite AR-C124910XX in the microsomal enzyme incubation system was determined by LC-MS/MS.The main enzymatic kinetic parameters K_m,V_max,CL_int were calculated using Prism5.After obtaining K_m,the concentration of the substrate ticagrelor in the reaction system was chosen to be three concentrations in the range of 1/3K_m³K_m..The concentration of simvastatin,lovastatin and atovava statins ranged from 1-100?M,and its metabolic interaction with ticagrelor was studied by in vitro rat liver microsomal metabolism assay.The reversible inhibition constant K_i of simvastatin on ticagrelor metabolism was calculated according to the Dixon formula using the SigmaPlot 12.3 enzyme kinetics module,and the most consistent model was selected based on the standard deviation.Results:The metabolism of ticagrelor in rat liver microsomes is consistent with the enzyme kinetics of substrate inhibition.The K_m value of AR-C124910XX is 24.83?M,and V_max is 159.6 pmol·min^-1 mg.^-1 protein.The apparent clearance rate(Cl_int)was 6.42 nL·min^-1·mg^-1 protein;simvastatin significantly inhibited the production of tigrisin active metabolites,and its inhibition was consistent with competitive reversible inhibition,and the inhibition constant Ki is 5.8?M.Lovastatin and atorvastatin exhibited moderate intensity inhibition of ticagrelor with inhibition constants of 11.4?M and 10.3?M,respectively.Conclusions:1.The metabolism of ticagrelor in rat liver microsomes is consistent with the enzyme kinetics of substrate inhibition.2.Simvastatin has a significant degree of metabolic inhibition of ticagrelor,and lovastatin and atorvastatin have a moderate inhibitory effect on ticagrelor.Clinically,ticagrelor needs to consider its interaction with simvastatin when it is combined with statins.