BackgroundWhile aspirin is a well‐established and generally effective anti‐platelet agent, considerable inter‐individual variation in drug response exists, for which mechanisms are not completely understood. Metabolomics allows for extensive measurement of small molecules in biological samples, enabling detailed mapping of pathways involved in drug response.Methods and ResultsWe used a mass‐spectrometry‐based metabolomics platform to investigate the changes in the serum oxylipid metabolome induced by an aspirin intervention (14 days, 81 mg/day) in healthy subjects (n=156). We observed a global decrease in serum oxylipids in response to aspirin (25 metabolites decreased out of 30 measured) regardless of sex. This decrease was concomitant with a significant decrease in serum linoleic acid levels (−19%, P=1.3×10−5), one of the main precursors for oxylipid synthesis. Interestingly, several linoleic acid‐derived oxylipids were not significantly associated with arachidonic‐induced ex vivo platelet aggregation, a widely accepted marker of aspirin response, but were significantly correlated with platelet reactivity in response to collagen.ConclusionsTogether, these results suggest that linoleic acid‐derived oxylipids may contribute to the non‐COX1 mediated variability in response to aspirin. Pharmacometabolomics allowed for more comprehensive interrogation of mechanisms of action of low dose aspirin and of variation in aspirin response.

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