Plasma miR-142 accounting for the missing heritability of CYP3A4/5 functionality is associated with pharmacokinetics of clopidogrel

Pharmacogenomics. 2016 Sep;17(14):1503-17. doi: 10.2217/pgs-2016-0027. Epub 2016 Aug 24.

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 Cmax (r = -0.5269; p = 0.0040) and associated with H4 AUC0-4h (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: CYP3A; clopidogrel; microRNA; pharmacokinetics.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Clopidogrel
  • Coronary Disease / drug therapy
  • Cytochrome P-450 CYP3A / genetics*
  • Female
  • Humans
  • Liver / enzymology
  • Male
  • MicroRNAs / blood*
  • Middle Aged
  • Platelet Aggregation Inhibitors / pharmacokinetics*
  • RNA, Messenger / analysis
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / pharmacokinetics

Substances

  • MIRN142 microRNA, human
  • MicroRNAs
  • Platelet Aggregation Inhibitors
  • RNA, Messenger
  • Clopidogrel
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ticlopidine