Original ArticleEnhanced Platelet Response to Clopidogrel in Abcc3-deficient Mice Due to Its Increased BioactivationTai, Ting MS*; Mi, Qiong-Yu PhD*; Ji, Jin-Zi PhD*; Yin, Qian BS*; Pan, Yu-Qin MS*; Zhang, Meng-Ran BS*; Huang, Bei-Bei BS*; Xie, Hong-Guang MD, PhD*,†,‡Author Information *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. Reprints: Hong-Guang Xie, MD, PhD, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, 68 Changle Rd, Nanjing 210006, China (e-mail: [email protected]). The authors report no conflicts of interest. T. Tai and Q.-Y. Mi contributed equally to this work. Journal of Cardiovascular Pharmacology: December 2016 - Volume 68 - Issue 6 - p 433-440 doi: 10.1097/FJC.0000000000000428 Buy Metrics 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. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.