The Effect Of Interleukin-10 On Clopidogrel Metabolic Activation And Platelet Reaction

Background:Elevated plasma interleukin-10(IL-10)levels were observed in patients who responded less to clopidogrel(a prodrug that is required for further metabolic bioactivation in the liver).However,no direct relationship was established between IL-10 and altered responsiveness to clopidogrel.Objective:To systematically explore possible differences in the formation of and response to clopidogrel active metabolite(CAM)in mice with or without IL-10 gene expression.Methods:(1)A single oral dose of clopidogrel(10 mg/kg)was given to IL-10 knockout(KO)and wild-type(WT)mice,respectively,and plasma concentrations and pharmacokinetic parameters of clopidogrel and CAM were measured and calculated.(2)ADP-induced whole-blood platelet aggregation was measured in KO and WT mice at 60 min after receiving 0,5,10,or 20 mg/kg of clopidogrel,respectively.(3)A single oral dose of clopidogrel(5 mg/kg)was given to KO and WT mice,and ADP-induced whole-blood platelet aggregation was monitored at 45,60,75,and 120 min after dosing,respectively.(4)Responders and non-responders of clopidogrel were identified for 188 elective PCI patients taking clopidogrel according to ADP-induced whole-blood platelet aggregation,and plasma IL-10 levels were measured with a commercial ELISA kit.Results:(1)Compared with IL-10 KO mice,WT mice had significantly lower area under the plasma concentration-time curve(AUC)of CAM as a result of a shorter mean elimination half-life,but had significantly higher AUC of clopidogrel due to slower systemic clearance and smaller volume of distribution.Although AUC of CAM was significantly lower in WT mice than in KO mice,their maximum plasma concentrations(Cmax)of CAM were not significantly different.(2)There were no significant differences in the extent of inhibition of ADP-induced platelet aggregation over baseline between KO and WT mice receiving 5,10 or 20 mg/kg clopidogrel,respectively.(3)There were no marked differences in inhibition of ADP-induced platelet aggregation by clopidogrel between KO and WT mouse groups at 45,60,75,120 min after dosing 5 mg/kg clopidogrel,respectively.(4)Plasma IL-10 levels did not differ significantly between responders and non-responders of clopidogrel in clinical settings.Conclusions:IL-10 does not modulate maximum plasma levels of clopidogrel active metabolite and its antiplatelet effects in mice.