Ticagrelor Does Not Inhibit Adenosine Transport at Relevant Concentrations: A Randomized Cross-Over Study in Healthy Subjects In Vivo

PLoS One. 2015 Oct 28;10(10):e0137560. doi: 10.1371/journal.pone.0137560. eCollection 2015.

Abstract

Background and purpose: In patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We now investigated the effects of ticagrelor on the adenosine system in humans in vivo.

Experimental approach: In a double-blinded, placebo-controlled cross-over trial in 14 healthy subjects, we have tested whether ticagrelor (180 mg) affects adenosine- and dipyridamole-induced forearm vasodilation, as surrogates of nucleoside uptake inhibition and adenosine formation, respectively. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was measured. Primary endpoint was adenosine-induced vasodilation.

Key results: Ticagrelor did not affect adenosine- or dipyridamole-induced forearm vasodilation. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was not affected by ticagrelor. In vitro, ticagrelor dose-dependently inhibited nucleoside uptake, but only at supra-physiological concentrations.

Conclusion and implications: In conclusion, at relevant plasma concentration, ticagrelor does not affect adenosine transport, nor adenosine formation in healthy subjects. Therefore, it is unlikely that this mechanism is a relevant pleiotropic effect of ticagrelor.

Trial registration: ClinicalTrials.gov NCT01996735.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / blood
  • Adenosine / metabolism*
  • Adenosine / pharmacology
  • Area Under Curve
  • Biological Transport / drug effects
  • Cell Separation
  • Cross-Over Studies
  • Erythrocytes / drug effects
  • Erythrocytes / metabolism
  • Forearm / blood supply
  • Healthy Volunteers*
  • Humans
  • Plethysmography
  • Ticagrelor
  • Uridine / metabolism
  • Veins / pathology
  • Young Adult

Substances

  • Ticagrelor
  • Adenosine
  • Uridine

Associated data

  • ClinicalTrials.gov/NCT01996735

Grants and funding

The study is conducted with financial support from AstraZeneca. NPR is a recipient of a dr. Dekker grant from the Netherlands Heart Foundation and a clinical fellowship from the Dutch Organisation for Health Research and Development (ZonMw). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.