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

Autor: van den Berg TN; Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands., El Messaoudi S; Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands., Rongen GA; Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands; Department of Internal Medicine (division of vascular medicine), Radboud university medical center, Nijmegen, The Netherlands., van den Broek PH; Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands., Bilos A; Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands., Donders AR; Department for Health Evidence, Radboud university medical center, Nijmegen, The Netherlands., Gomes ME; Department of Cardiology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands., Riksen NP; Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands; Department of Internal Medicine (division of vascular medicine), Radboud university medical center, Nijmegen, The Netherlands.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2015 Oct 28; Vol. 10 (10), pp. e0137560. Date of Electronic Publication: 2015 Oct 28 (Print Publication: 2015).
DOI: 10.1371/journal.pone.0137560
Abstrakt: 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.
Databáze: MEDLINE
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