Open AccessPharmacometabolomics Reveals That Serotonin Is Implicated in Aspirin Response Variability
Author(s) -
ElleroSimatos S,
Lewis JP,
Georgiades A,
YergesArmstrong LM,
Beitelshees AL,
Horenstein RB,
Dane A,
Harms AC,
Ramaker R,
Vreeken RJ,
Perry CG,
Zhu H,
Sànchez CL,
Kuhn C,
Ortel TL,
Shuldiner AR,
Hankemeier T,
KaddurahDaouk R
Publication year - 2014
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1038/psp.2014.22
Subject(s) - aspirin , platelet , serotonin , platelet activation , incubation , ex vivo , medicine , endocrinology , pharmacology , chemistry , in vitro , biochemistry , receptor
While aspirin is generally effective for prevention of cardiovascular disease, considerable variation in drug response exists, resulting in some individuals displaying high on‐treatment platelet reactivity. We used pharmacometabolomics to define pathways implicated in variation of response to treatment. We profiled serum samples from healthy subjects pre‐ and postaspirin (14 days, 81 mg/day) using mass spectrometry. We established a strong signature of aspirin exposure independent of response (15/34 metabolites changed). In our discovery ( N = 80) and replication ( N = 125) cohorts, higher serotonin levels pre‐ and postaspirin correlated with high, postaspirin, collagen‐induced platelet aggregation. In a third cohort, platelets from subjects with the highest levels of serotonin preaspirin retained higher reactivity after incubation with aspirin than platelets from subjects with the lowest serotonin levels preaspirin (72 ± 8 vs. 61 ± 11%, P = 0.02, N = 20). Finally, ex vivo , serotonin strongly increased platelet reactivity after platelet incubation with aspirin (+20%, P = 4.9 × 10 −4 , N = 12). These results suggest that serotonin is implicated in aspirin response variability. CPT Pharmacometrics Syst. Pharmacol . (2014) 3, e125; doi: 10.1038/psp.2014.22 ; published online 16 July 2014