CYP2C19 and CYP3A4 activity and ADP-induced platelet reactivity in prasugrel- or ticagrelor-treated STEMI patients: monocentric study in PRAGUE-18 trial participants

Abstract

1. We assessed the contribution of CYP2C19 and CYP3A4 metabolic activity to the ADP-induced platelet aggregation 1h and 24h after a loading dose of 60 mg prasugrel or 180 mg ticagrelor in patients with ST-elevation myocardial infarction (STEMI). Further, we assessed the contribution of CYP2C19 polymorphisms and medication to the CYP enzymatic activity.

2. Patients with STEMI were randomly assigned to the treatment with prasugrel (n = 51) or ticagrelor (n = 46). Metabolic activity of CYP2C19 and CYP3A4 was assessed by the rate of 5-hydroxylation and sulfoxidation of lansoprazole. Further, patients were genotyped for CYP2C19 *2 and *17 alleles.

3. In prasugrel-treated patients, high ADP-induced platelet reactivity 1h after the loading dose positively correlated with 5OH-lansoprazole/lansoprazole ratio (r = 0.44, p = 0.002), a marker of CYP2C19 metabolic activity, and negatively with lansoprazole-sulfone/lansoprazole ratio, which reflects CYP3A4 metabolic activity (r = −0.35, p = 0.018).

4. CYP2C19 poor metabolizers had lower 5OH-lansoprazole/lansoprazole ratio and higher lansoprazole-sulfone/lansoprazole ratio, but without any effect on the ADP-induced platelet reactivity. The treatment with amiodarone, a CYP3A4 inhibitor, influenced neither the metabolic ratios nor the ADP-induced platelet reactivity.

5. The CYP3A4 and CYP2C19 metabolic activity is associated with ADP-induced platelet reactivity in prasugrel-treated, but not ticagrelor-treated patients with STEMI.

Keywords:

• Cytochrome P450
• prasugrel
• ticagrelor
• ADP test
• aggregation
• lansoprazole

Acknowledgments

The authors thank to Markéta Beranová for the help with sample collection, and further to Lucie Kolaříková and Jiří Šikula for their laboratory work during the genetic analyses.

Author contributions

J.M. designed the presented study, collected the data, performed the statistical analysis and wrote the manuscript. O.H. was responsible for the management of patients and sample collection. K.K. and O.P. optimized and performed the HPLC analyses. A.M. initiated the study and made important contributions to general study design. Z.S. optimized and performed the genetic analyses. Z.M. conducted the original PRAGUE 18 study, which was used for the patients’ recruitment. J.J. designed the HPLC analyses and wrote parts of the “Methods” section.

Disclosure statement

The authors report no conflict of interest.

Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent was obtained from all individual participants included in the study.

Statement of originality

The manuscript describes original research that has only been published in the form of conference abstract at the 86th Congress of the European Atherosclerosis Society (EAS). The conference abstract is available in Atherosclerosis journal and in Web of Science under accession number 000442512600260. There are several minor differences in this manuscript, most notably the extension of the study group by several patients. However, its main findings are the same.

Data availability statement

The patients’ data that support the findings of this study are available from Saint Anne’s University Hospital, Brno, but restrictions regarding the data protection policy apply to the availability of these data, so they are not publicly available. Data are, however, available from the authors upon reasonable request.

Additional information

Funding

This work was supported by Project No. LQ1605 from the National Program of Sustainability II (MEYS CR), by the grant of Ministry of Health of CR MUNI/A/1132/2017 and by funds from the Faculty of Medicine, Masaryk University to a junior researcher O.P.