Plasma MIR-142 Accounting for the Missing Heritability of CYP3A4/5 Functionality is Associated with Pharmacokinetics of Clopidogrel

Abstract

Aim: To investigate whether plasma miRNAs targeting CYP3A4/5 have an impact on the variance of pharmacokinetics of clopidogrel. Materials & methods: The contribution of 13 miRNAs to the CYP3A4/5 gene expression and activity was investigated in 55 liver tissues. The association between plasma miRNAs targeting CYP3A4/5 mRNA and clopidogrel pharmacokinetics was analyzed in 31 patients with coronary heart disease who received 300 mg loading dose of clopidogrel. Results: Among 13 miRNAs, miR-142 was accounting for 12.2% (p = 0.002) CYP3A4 mRNA variance and 9.4% (p = 0.005) CYP3A5 mRNA variance, respectively. Plasma miR-142 was negatively associated with H4 C_max (r = -0.5269; p = 0.0040) and associated with H4 AUC_0–4h (r = -0.4986; p = 0.0069) after 300 mg loading dose of clopidogrel in coronary heart disease patients. Conclusion: miR-142 could account for a part of missing heritability of CYP3A4/5 functionality related to clopidogrel activation.

Keywords::

• clopidogrel
• CYP3A
• microRNA
• pharmacokinetics

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Acknowledgements

We appreciate Gilles Tuffal, George Liu and their colleagues of Sanofi-Aventis for kindly offering the 3′-methoxyacetophenone derivatives (MP-H3 [SAR287550–1] and MP-H4 [SAR206251]) of free clopidogrel active metabolite stereoisomers (H3 and H4).

Financial & competing interests disclosure

This work was supported by the National Key Technology R&D Program of China (no. 2011BAI11B07), and the National Nature Science Foundation of China (no. 81373486, 81200825, 81673689), and Science and Technology Development Projects of Guangdong Province, China (no. 2013B021800157). This work was also supported by Department of Education of Guangdong Province Special and Innovative Project for Natural Sciences (no. 2015KTSCX073), Science and Technology Development Projects of Guangzhou, Guangdong, China (201510010236) and Innovative and strong project of Guangdong Pharmaceutical University (2015cxqx153). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

This study was approved by the Medical Ethical Review Committee of Sun Yat-Sen Memorial Hospital (Guangzhou, China) and Guangdong General Hospital (Guangzhou, China). Written informed consent was obtained from each patient.

Additional information

Funding

This work was supported by the National Key Technology R&D Program of China (no. 2011BAI11B07), and the National Nature Science Foundation of China (no. 81373486, 81200825, 81673689), and Science and Technology Development Projects of Guangdong Province, China (no. 2013B021800157). This work was also supported by Department of Education of Guangdong Province Special and Innovative Project for Natural Sciences (no. 2015KTSCX073), Science and Technology Development Projects of Guangzhou, Guangdong, China (201510010236) and Innovative and strong project of Guangdong Pharmaceutical University (2015cxqx153). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.