Antagonism of P2Y₁₂ reduces physiological thromboxane levels.
Antiplatelet therapy for the management of patients with cardiovascular risks often includes a combination therapy of aspirin and clopidogrel, acting through inhibition of thromboxane generation and blockade of G(i)-coupled P2Y₁₂ receptor, respectively. We hypothesized that ADP acting through P2Y₁₂ regulates physiological thromboxane levels. The serum thromboxane levels in mice (n = 3) dosed with clopidogrel and prasugrel were decreased by 83.1 ± 5.3% and 94.26 ± 1.75% respectively compared to untreated mice. Pre-treatment of human blood (n = 3) ex vivo with active metabolites of clopidogrel or prasugrel led to a reduction in thromboxane levels to 16.3 ± 3.2% and 4.9 ± 0.8% respectively, compared to untreated human serum. We also evaluated serum thromboxane levels in P2Y receptor null mice (n = 4). Whereas serum thromboxane levels in P2Y₁ null mice were similar to those in wild type littermates, those in the P2Y₁₂ null mice were inhibited by 83.15 ± 3.8%. Finally, in a pilot study, serum thromboxane levels were reduced by 76.05 ± 8.41% in healthy human volunteers (n = 6) upon dosing with clopidogrel, compared to the levels before dosing. In conclusion, P2Y₁₂ antagonism alone can decrease physiological thromboxane levels. Thus, this study could pave way the for newer/modified treatment regimens for the management of patients with thrombotic complications who are allergic or non-responsive to aspirin.
Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Kamala
K
Bhavaraju
Alexander
A
Georgakis
Jianguo
J
Jin
Theodore Kent
TK
Gartner
Yoshiaki
Y
Tomiyama
Alan
A
Nurden
Paquita
P
Nurden
Satya P
SP
Kunapuli
D000244:Adenosine Diphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D000077144:Clopidogrel; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010865:Pilot Projects; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D000068799:Prasugrel Hydrochloride; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics / Q000378:metabolism*; D013876:Thiophenes; D013931:Thromboxanes / Q000097:blood*; D013988:Ticlopidine / Q000031:analogs & derivatives; D055815:Young Adult
D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; D013931:Thromboxanes; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine