The Influence Of Inflammatory Factor IL-6 On The Metabolism And Response Of Clopidogrel

Background and aims:Coronary heart disease is generally thought to be a class of chronic inflammatory disease,in which proinflammatory cytokine interleukin-6(IL-6)is involved.In this clinical setting,clopidogrel(CLP),alone or in combination with aspirin,is most frequently used to prevent either recurrent cardiac ischemia in patients with acute coronary syndrome or the occurrence and development of stent thrombosis in those undergoing percutaneous coronary intervention for stenting,consequently reducing their risk.As a prodrug,CLP undergoes metabolic inactivation(hydrolysis)catalyzed by carboxylesterase 1(CES1)and metabolic activation catalyzed by several cytochrome P450s(e.g.CYP3A4,CYP1A2,CYP2C19,CYP2B6,and CYP2C9)before it exerts antiplatelet effects.In human liver,the majority of CLP is hydrolyzed by CES1 to generate inactive CLP carboxylate(CLP-C),while only 15%was metabolized to CLP active metabolite(CAM)by CYP450s.Earlier studies indicated that IL-6 can inhibit not only CES1 but also the above-mentioned P450s in vitro.However,no data are available showing the effects of IL-6 on the metabolic activation of and platelet response to CLP in vivo.This study was designed to decipher the effects of IL-6 on the metabolism of and platelet response to clopidogrel in wild-type(WT)versus IL-6 knock-out(KO)mice.Methods:IL-6 WT and KO mice were treated with CLP by gavage at a single oral dose of 5,10,or 20 mg/kg,and blood samples were drawn from orbital venous plexus at 5,10,30,45,75,120,180 and 300 min after dosing,respectively.The plasma concentrations of CLP,CAM-H4,and CLP-C were determined by LC-MS/MS,and their pharmacokinetic parameters were calculated.In order to further investigate the differences in platelet response to CLP between WT and IL-6 KO mice,either of mice was treated with CLP by gavage at a single dose of 0(vehicle control),5,10,or 20 mg/kg,and blood samples were obtained at 1 h after dosing,respectively.ADP-induced whole-blood platelet aggregation was measured and inhibition of platelet aggregation by CLP was calculated.Moreover,the expression level of activated αIIbβ3 complex was monitored using two-color flow cytometry,and inhibition of platelet activation by CLP was calculated.Results:Compared with WT mice,IL-6 KO mice exhibited similar systematic exposure(e.g.AUC,and Cmax)to CLP,CAM-H4,and CLP-C for each dose of CLP,but such systematic exposure increased with the dose of CLP significantly.In addition,inhibition of ADP-induced whole-blood platelet aggregation and platelet activation by CLP was dose-dependent,but there was no marked difference in the platelet response between WT and IL-6 KO mice for each dose of CLP,respectively.Conclusions:The presence or absence of IL-6 does not affect the metabolism of and response to CLP in mice.