Oxylipid Profile of Low-Dose Aspirin Exposure: A Pharmacometabolomics Study

Abstract

Background: While 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 results: We 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.

Conclusions: Together, 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.

Keywords: aspirin; drugs; fatty acids; lipids; pharmacology; platelets.

Figure 1

Procedures for sample selection. Flow diagram shows procedure for sample selection for the 156 metabolomics substudy participants from the overall Heredity and Phenotype Intervention (HAPI) Heart Study (n=745).

Figure 2

Effect of aspirin on oxylipids. Metabolites detected in our study samples are in bold. Metabolites significantly changed upon aspirin treatment are circled and color coded according to their percentage change upon aspirin treatment: red: change >−60%; orange: −60%> change >−25%; yellow: −25%> change >0%. COX indicates cyclooxygenase; CYP, cytochrome P‐450 monooxygenases; EpETrE, epoxyeicosatrienoic acid; LOX, lipoxygenases; TXA, thromboxane A2; PGH2: prostaglandin H2, PGF2: prostaglandin F2, PGFS: prostaglandin F synthase, PLA2: phospholipase A2.

Figure 3

Correlations between oxylipids. A, Spearman correlation coefficients for correlation between metabolite levels pre‐aspirin in all 156 subjects are displayed. Metabolites were clustered based on Spearman correlation coefficients using modulated modularity clustering algorithm. B, Spearman correlation coefficients for correlation between metabolite levels post aspirin in all 156 subjects are displayed. The clustering order is the same as in Figure 3A. C, Q values evaluating the significance of the change in correlation between metabolites post‐ vs pre‐aspirin are displayed. The clustering order is the same as in Figure 3A.

Figure 4

Typical correlations between oxylipid levels pre‐aspirin and their precursor fatty acid levels pre‐aspirin. Correlations between (A) linoleic acid (LA) and 9‐HODE (LA‐derived oxylipid) and (B) arachidonic acid (AA) and 5‐HETE (AA‐derived oxylipid).