In Vitro Metabolism of Ticagrelor and Its Metabolic Interactions with Statins
XUE Ying1, ZHAO Yi-bo1, WANG Zi-teng2, CAI Wei-min2, LIU Shuai-bing1*
1. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; 2. School of Pharmacy, Fudan University, Shanghai 201203, China
Abstract：OBJECTIVE To study the in vitro metabolism of ticagrelor and investigate the drug-drug interactions between ticagrelor and some commonly used statins (simvastatin, lovastatin and atorvastatin), expecting to provide some useful information for the rational use of ticagrelor in clinic. METHODS The metabolic reaction of ticagrelor was performed in rat liver microsomes. After incubation for a given time, the reactions were stopped with methanol, as well as to precipitate the protein. For drug-drug interactions study, statins (simvastatin, lovastatin and atorvastatin) were selected, the interactions between ticagrelor and these drugs were explored in vitro using rat liver microsomes. The concentrations of ticagrelor active metabolite, AR-C124910XX in the incubation system were determined by a validated LC-MS/MS method. The main enzyme kinetic parameters Km, Vmax and CLint were calculated using Prism 5 software. After Km was obtained, the concentrations of the substrate ticagrelor in the reaction system were selected as three concentrations in the range of 1/3Km-3Km, and the concentrations of simvastatin, lovastatin and atorvastatin were in the range of 1-100 μmol·L-1. The metabolic interactions with ticagrelor were investigated by in vitro rat liver microsomal metabolism assays. The reversible inhibition constant Ki for each statin against ticagrelor metabolism was calculated according to the Dixon formula utilizing the SigmaPlot 12.3 software enzyme kinetics module, and the model that best fits was selected based on the standard deviation. RESULTS The metabolism of ticagrelor in rat liver microsomes was in accordance with Michaelis-Menten enzymatic kinetics. The Km value of ticagrelor transformed to AR-C124910XX was 32.2 μmol·L-1, and Vmax was 149.0 pmol·min-1·mg(pro)-1. The apparent clearance rate, CLint was 4.63 nL·min-1·mg(protein)-1. Drug-Drug interaction studies indicated that simvastatin significantly inhibited the production of ticagrelor active metabolite, and its inhibition was consistent with mixed inhibition with an inhibition constant Ki of 0.58 μmol·L-1, α of 7.5 and β of 0.56. Lovastatin and atorvastatin showed moderate mixed inhibition of ticagrelor with inhibition constants Ki of 2.9 and 7.5 μmol·L-1, α of 3 and 1.7, β of 0.34 and 0.29, respectively. CONCLUSION The metabolism of ticagrelor in rat liver microsomes are in accordance with Michaelis-Menten kinetics. Simvastatin inhibits the metabolism of ticagrelor significantly in a concentration dependent manner. Lovastatin and atorvastatin exhibit moderate inhibition of ticagrelor. When ticagrelor is prescribed in combination with these statin drugs, the interactions of them should not be ignored in clinic, especially for simvastatin.
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XUE Ying, ZHAO Yi-bo, WANG Zi-teng, CAI Wei-min, LIU Shuai-bing. In Vitro Metabolism of Ticagrelor and Its Metabolic Interactions with Statins. Chinese Pharmaceutical Journal, 2020, 55(23): 1962-1968.
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2020, Vol. 55 
