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Amlodipine – not a significant contributor to clopidogrel non-response?
  1. Rolf P Kreutz1,2,
  2. David A Flockhart2
  1. 1Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
  2. 2Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA
  1. Correspondence to Dr Rolf P Kreutz, Krannert Institute of Cardiology, Indiana University School of Medicine, 1800 N. Capitol Ave, ME-400, Indianapolis, IN 46202, USA; rkreutz{at}

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The current study by Li et al1 examines the pharmacodynamic interaction of amlodipine and clopidogrel. Dual antiplatelet therapy with aspirin and clopidogrel is standard of care for patients with coronary stenting and acute coronary syndromes, although newer, more potent P2Y12 inhibitors such as prasugrel and ticagrelor have recently become available. Clopidogrel is a prodrug that is metabolised in a two-step process by cytochrome P450 (CYP) and esterases to its principal metabolites (figure 1).2 Large interpatient variability has been observed in pharmacodynamic studies of clopidogrel response and pharmacokinetic studies measuring active clopidogrel thiol metabolites. Among the CYP450 isoforms, CYP2C19, CYP3A4, CYP2C9 and CYP2B6 have been identified as being involved in the second step of 2-oxo clopidogrel metabolism and active thiol formation. A variety of esterases are thought to mediate inactivation of parent clopidogrel and metabolites, thus influencing the availability of active thiol metabolite and eventually the pharmacodynamic response to clopidogrel. The term ‘clopidogrel non-response’ has been used to describe persistent high ADP induced platelet reactivity during treatment with clopidogrel and has been defined by various ex vivo assays.

Figure 1

Metabolism of clopidogrel by cytochrome P450 isoenzymes and esterases.

The importance of individual CYP450 enzymes in clopidogrel metabolism to its active form has been illustrated by the finding that carriers of CYP2C19*2 polymorphisms who are treated with clopidogrel after coronary stenting are at increased risk of adverse thrombotic events.3 This enzyme is vulnerable to drug-drug interactions, as are other CYP450 isoforms involved in clopidogrel metabolism. Many drugs that are commonly prescribed to patients with coronary artery disease happen to interact with these enzymes. Statins, some of which are metabolised by CYP3A4, and proton pump inhibitors, which are often metabolised by CYP2C19 have received particular attention as concerns have surfaced regarding …

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  • Contributors Both authors contributed substantially to the writing of this editorial. RPK is responsible for the overall content as guarantor.

  • Funding DAF is supported by NIH grant T32GM008425.

  • Competing interests None.

  • Provenance and peer review Commissioned; internally peer reviewed.

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