title: Interleukin-10 does not modulate clopidogrel platelet response in mice.
abstract: ESSENTIALS: It is unclear whether interleukin-10 (IL-10) could affect clopidogrel metabolism and response. The bioactivation of and response to clopidogrel were determined between mice with or without IL-10. Maximum clopidogrel active metabolite levels were the major driver of platelet response to clopidogrel. IL-10 did not modulate maximum levels of clopidogrel active metabolite and its antiplatelet effects.
  
  
  CONCLUSIONS
  
  
  
  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 data are currently available suggesting whether there is such an association.
  
  
  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
  A single oral dose of clopidogrel (10 mg kg(-1)) was given to IL-10 knockout (KO) mice and wild-type (WT) control mice, respectively, and pharmacokinetic parameters of clopidogrel and CAM were calculated. Moreover, adenosine diphosphate-induced whole-blood platelet aggregation was measured in mice receiving 0, 5, 10, or 20 mg kg(-1) of clopidogrel, respectively.
  
  
  RESULTS
  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, antiplatelet effects of clopidogrel did not differ significantly between the two mouse groups, as their maximum plasma concentrations (Cmax ) of CAM were not significantly different.
  
  
  CONCLUSIONS
  IL-10 expression level affects AUC rather than Cmax of CAM, but the Cmax of CAM is the major driver of antiplatelet effects of clopidogrel in mice.
authors.affiliation: General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Yin
authors.affiliation: General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: T
authors.initials: T
authors.lastname: Tai
authors.affiliation: General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: J-Z
authors.initials: JZ
authors.lastname: Ji
authors.affiliation: General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Q-Y
authors.initials: QY
authors.lastname: Mi
authors.affiliation: General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: M-R
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Department of Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: W-J
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: Division of Nephrology, Department of Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: C-C
authors.initials: CC
authors.lastname: Cao
authors.affiliation: General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Pharmacology, Nanjing Medical University School of Pharmacy, Nanjing, Jiangsu, China.
authors.forename: H-G
authors.initials: HG
authors.lastname: Xie
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D019540:Area Under Curve; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000077144:Clopidogrel; D005838:Genotype; D016753:Interleukin-10 / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D008657:Metabolic Clearance Rate; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010979:Platelet Function Tests; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C556062:IL10 protein, mouse; D010975:Platelet Aggregation Inhibitors; D016753:Interleukin-10; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: clopidogrel; hemostasis; interleukin-10; mice; platelet aggregation