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


METHODS
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.


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.


CONCLUSIONS
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.


BACKGROUND
ClinicalTrials.gov NCT01996735.
Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands.
T N A
TN
van den Berg
Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands.
S
S
El Messaoudi
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.
G A
GA
Rongen
Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands.
P H H
PH
van den Broek
Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands.
A
A
Bilos
Department for Health Evidence, Radboud university medical center, Nijmegen, The Netherlands.
A R T
AR
Donders
Department of Cardiology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
M E
ME
Gomes
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.
N P
NP
Riksen
D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D019540:Area Under Curve; D001692:Biological Transport / Q000187:drug effects; D002469:Cell Separation; D018592:Cross-Over Studies; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005542:Forearm / Q000098:blood supply; D064368:Healthy Volunteers; D006801:Humans; D010991:Plethysmography; D000077486:Ticagrelor; D014529:Uridine / Q000378:metabolism; D014680:Veins / Q000473:pathology; D055815:Young Adult
D000077486:Ticagrelor; D000241:Adenosine; D014529:Uridine