Xia-Qin Wang1, Chen-Lin Shen2, Bang-Ning Wang3, Xiao-Hui Huang4, Zhang-le Hu5, Jun Li6. 1. Division of Cardiology, The First Affiliated Hospital, Anhui Medical University, Hefei 230032, China; Division of Cardiology, The Fourth Affiliated Hospital, Anhui Medical University, Hefei 230032, China. 2. Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032, China. 3. Division of Cardiology, The First Affiliated Hospital, Anhui Medical University, Hefei 230032, China. Electronic address: wangbangning@medmail.com.cn. 4. Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: mathdrug@sina.com. 5. Division of Cardiology, The Second Affiliated Hospital, Anhui Medical University, Hefei 230032, China. 6. Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
Abstract
BACKGROUNDS AND OBJECTIVES: Clopidogrel, an inhibitor of platelet ADP P2Y12 receptors, plays an important role in the prevention of stent thrombosis. However, some patients do not attain adequate antiplatelet effects. Studies have shown that the genetic variation in CYP2C19*2 is associated with an impaired response to clopidogrel. This study was designed to investigate the genetic variants of 21 genes involving in the absorption, metabolism, and pharmacodynamics of clopidogrel. The effects of these genes on the plasma level of clopidogrel and its metabolites (active clopi-H4 and inactive CLPM) and platelet reactivity were also studied. METHODS AND RESULTS: 401 acute coronary syndrome (ACS) patients received either a 300 mg loading dose following 75 mg maintenance dose daily or a 75mg maintenance dose daily of clopidogrel. The inhibition of platelets was assessed using light transmittance aggregometry. Plasma concentrations of clopidogrel as well as its active (clopi-H4) and inactive (CLPM) metabolites were measured using HPLC-MS-MS method. Among 21 genes, the carriers of CYP2C19*2 were associated with lower exposure to its active (clopi-H4) and inactive (CLPM) metabolites (both P<0.05 vs. non-carriers) and thus decreased platelet inhibition (P<0.05 vs. non-carriers). Notably, the carriers of ABCB1 C3435T were associated with lower levels of plasma clopidogrel and its active (clopi-H4) and inactive (CLPM) metabolites (all P<0.05 vs. non-carriers) which also correlated with subsequently decreased platelet inhibition (P<0.05 vs. non-carriers). There were no obvious effects of other studied genes on clopidogrel. CONCLUSIONS: CYP2C19*2 is a determinant for the formation of the active metabolite of clopidogrel and its antiplatelet effects. Meanwhile, ABCB1 C3435T plays an important role in intestinal absorption of clopidogrel which further affects the exposure to the active metabolite of clopidogrel and platelet aggregation.
BACKGROUNDS AND OBJECTIVES:Clopidogrel, an inhibitor of platelet ADP P2Y12 receptors, plays an important role in the prevention of stent thrombosis. However, some patients do not attain adequate antiplatelet effects. Studies have shown that the genetic variation in CYP2C19*2 is associated with an impaired response to clopidogrel. This study was designed to investigate the genetic variants of 21 genes involving in the absorption, metabolism, and pharmacodynamics of clopidogrel. The effects of these genes on the plasma level of clopidogrel and its metabolites (active clopi-H4 and inactive CLPM) and platelet reactivity were also studied. METHODS AND RESULTS: 401 acute coronary syndrome (ACS) patients received either a 300 mg loading dose following 75 mg maintenance dose daily or a 75mg maintenance dose daily of clopidogrel. The inhibition of platelets was assessed using light transmittance aggregometry. Plasma concentrations of clopidogrel as well as its active (clopi-H4) and inactive (CLPM) metabolites were measured using HPLC-MS-MS method. Among 21 genes, the carriers of CYP2C19*2 were associated with lower exposure to its active (clopi-H4) and inactive (CLPM) metabolites (both P<0.05 vs. non-carriers) and thus decreased platelet inhibition (P<0.05 vs. non-carriers). Notably, the carriers of ABCB1C3435T were associated with lower levels of plasma clopidogrel and its active (clopi-H4) and inactive (CLPM) metabolites (all P<0.05 vs. non-carriers) which also correlated with subsequently decreased platelet inhibition (P<0.05 vs. non-carriers). There were no obvious effects of other studied genes on clopidogrel. CONCLUSIONS:CYP2C19*2 is a determinant for the formation of the active metabolite of clopidogrel and its antiplatelet effects. Meanwhile, ABCB1C3435T plays an important role in intestinal absorption of clopidogrel which further affects the exposure to the active metabolite of clopidogrel and platelet aggregation.
Authors: Christian Schoergenhofer; Eva-Luise Hobl; Peter Schellongowski; Gottfried Heinz; Walter S Speidl; Jolanta M Siller-Matula; Monika Schmid; Raute Sunder-Plaßmann; Thomas Stimpfl; Matthias Hackl; Bernd Jilma Journal: Clin Pharmacol Ther Date: 2017-11-03 Impact factor: 6.875
Authors: Cristina Lucía Dávila-Fajardo; Xando Díaz-Villamarín; Alba Antúnez-Rodríguez; Ana Estefanía Fernández-Gómez; Paloma García-Navas; Luis Javier Martínez-González; José Augusto Dávila-Fajardo; José Cabeza Barrera Journal: Genes (Basel) Date: 2019-04-01 Impact factor: 4.096