Enhanced platelet response to clopidogrel in Abcc3-deficient mice due to its increased bioactivation.

Resistance of the patient to clopidogrel (an inactive prodrug) has been recently reported to be associated with increased mRNA expression of ABCC3 that encodes MRP3 (multidrug resistance-associated protein 3). However, there is no evidence to show the effects of MRP3 on altered platelet responses to clopidogrel and their underlying mechanisms. To further clarify whether the absence and presence of Mrp3 could affect the formation of and response to clopidogrel active metabolite (CAM) in Abcc3 knock-out (KO) vs. wild-type (WT) mice, we determined pharmacokinetic profiles of clopidogrel and CAM and measured inhibition of ADP-induced platelet aggregation by clopidogrel after administration of a single oral dose of clopidogrel to KO and WT mice, respectively. Results indicated that Abcc3 KO mice exhibited increased formation of CAM and greater systemic exposure to clopidogrel as well as enhanced inhibition of ADP-induced platelet aggregation ex vivo by clopidogrel when compared with well-matched WT mice. We conclude that Abcc3 KO mice have enhanced platelet response to clopidogrel due to increased formation of CAM.

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