title: Enhanced Platelet Response to Clopidogrel in Abcc3-deficient Mice Due to Its Increased Bioactivation.
abstract: Resistance of the patient to clopidogrel (an inactive prodrug) has been recently reported to be associated with increased messenger RNA expression of ABCC3 that encodes MRP3 (multidrug resistance-associated protein 3). However, there is no evidence showing the effects of MRP3 on altered platelet responses to clopidogrel and their underlying mechanisms. To further clarify whether the presence or absence of Mrp3 could affect the formation of and response to clopidogrel active metabolite (CAM) in Abcc3 knockout (KO) versus wild-type (WT) mice, we determined pharmacokinetic profiles of clopidogrel and CAM and measured inhibition of adenosine diphosphate-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 and enhanced inhibition of adenosine diphosphate-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.
authors.affiliation: *General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; †Department of Pharmacology, Nanjing Medical University School of Pharmacy, Nanjing, China; and ‡Department of Pharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Tai
authors.forename: Qiong-Yu
authors.initials: QY
authors.lastname: Mi
authors.forename: Jin-Zi
authors.initials: JZ
authors.lastname: Ji
authors.forename: Qian
authors.initials: Q
authors.lastname: Yin
authors.forename: Yu-Qin
authors.initials: YQ
authors.lastname: Pan
authors.forename: Meng-Ran
authors.initials: MR
authors.lastname: Zhang
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Huang
authors.forename: Hong-Guang
authors.initials: HG
authors.lastname: Xie
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency*; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000077144:Clopidogrel; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010975:Platelet Aggregation Inhibitors; D013988:Ticlopidine; C114462:multidrug resistance-associated protein 3