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. 2012 Sep 9;3(10):844-9.
doi: 10.1021/ml3002067. eCollection 2012 Oct 11.

Identification of the Significant Involvement and Mechanistic Role of CYP3A4/5 in Clopidogrel Bioactivation

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Free PMC article

Identification of the Significant Involvement and Mechanistic Role of CYP3A4/5 in Clopidogrel Bioactivation

Yaoqiu Zhu et al. ACS Med Chem Lett. .
Free PMC article

Abstract

The clinical response to the antiplatelet prodrug clopidogrel is associated with high intersubject variability and a certain level of therapeutic resistance. Previous studies have suggested that genetic polymorphism of CYP2C19 might be one determinant of clopidogrel efficacy and led to the CYP2C19 genotype-tailored antithrombotic therapy. However, evidence against the role of CYP2C19 from multiple studies implied the involvement of other factors. Here, we report that prodrug activation of the thiophene motif in clopidogrel is attenuated by heavy metabolic attrition of the piperidine motif. CYP3A4/5 was identified to be the enzyme metabolizing the piperidine motif. Inhibiting CYP3A4/5-mediated attrition was shown to potentiate active metabolite formation, which was found to be catalyzed by multiple CYP enzymes. Identifying the significant involvement of CYP3A4/5 and characterizing its mechanistic role in clopidogrel bioactivation might assist future pharmacogenomic studies in exploring the full mechanism underlying clopidogrel efficacy.

Keywords: Clopidogrel resistance, prodrug attrition, CYP3A4/5, active metabolite potentiation, piperidine metabolism.

Figures

Scheme 1
Scheme 1. Reported Metabolic Activation and Deactivation Pathways of Clopidogrel
Figure 1
Figure 1
Extracted ion chromatogram of clopidogrel incubation with HLM. (A) Sample without NADPH and (B) sample with NADPH. Nonlabeled peaks are extracted isotopic signals of other metabolite or background signals.
Figure 2
Figure 2
Fragmentation analysis and online H-D exchange experiment result of M0.
Scheme 2
Scheme 2. Proposed CYP-Catalyzed Metabolic Pathways of Clopidogrel
Figure 3
Figure 3
CYP phenotyping results of M2 (metabolic activation), M8 (thiophene metabolism), and M5 (piperidine metabolism) formation.
Figure 4
Figure 4
Selective inhibition of CYP3A4/5-catalyzed piperidine metabolism potentiates thiophene bioactivation.
Figure 5
Figure 5
Proposed pathways of clopidogrel active metabolite formation with multiple factors that could significantly impact prodrug efficacy.

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