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


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.
Analytical Biosciences Division, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.) Netherlands Metabolomics Centre, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.).
Sandrine
S
Ellero-Simatos
Program Personalized and Genomic Medicine, Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (A.L.B., J.P.L., L.M.Y.A., R.B.H., A.R.S.).
Amber L
AL
Beitelshees
Program Personalized and Genomic Medicine, Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (A.L.B., J.P.L., L.M.Y.A., R.B.H., A.R.S.).
Joshua P
JP
Lewis
Program Personalized and Genomic Medicine, Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (A.L.B., J.P.L., L.M.Y.A., R.B.H., A.R.S.).
Laura M
LM
Yerges-Armstrong
Duke University Medical Center, Durham, NC (A.G., R.K.D.).
Anastasia
A
Georgiades
Analytical Biosciences Division, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.) Netherlands Metabolomics Centre, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.).
Adrie
A
Dane
Analytical Biosciences Division, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.) Netherlands Metabolomics Centre, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.).
Amy C
AC
Harms
Analytical Biosciences Division, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.) Netherlands Metabolomics Centre, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.).
Katrin
K
Strassburg
Analytical Biosciences Division, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.) Netherlands Metabolomics Centre, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.).
Faisa
F
Guled
Analytical Biosciences Division, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.) Netherlands Metabolomics Centre, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.).
Margriet M W B
MM
Hendriks
Program Personalized and Genomic Medicine, Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (A.L.B., J.P.L., L.M.Y.A., R.B.H., A.R.S.).
Richard B
RB
Horenstein
Program Personalized and Genomic Medicine, Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (A.L.B., J.P.L., L.M.Y.A., R.B.H., A.R.S.).
Alan R
AR
Shuldiner
Analytical Biosciences Division, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.) Netherlands Metabolomics Centre, Leiden, The Netherlands (S.E.S., A.D., A.C.H., K.S., F.G., M.B.H., T.H.).
Thomas
T
Hankemeier
Duke University Medical Center, Durham, NC (A.G., R.K.D.) Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.D.) Duke Institute for Brain Sciences, Duke University, Durham, NC (R.K.D.) Institute of Genome Science and Policy, Durham, NC (R.K.D.).
Rima
R
Kaddurah-Daouk
D000284:Administration, Oral; D000328:Adult; D061365:Amish; D001241:Aspirin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D019787:Linoleic Acid / Q000097:blood; D008055:Lipids / Q000097:blood*; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D010084:Oxidation-Reduction; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D010979:Platelet Function Tests
D015415:Biomarkers; D008055:Lipids; D010975:Platelet Aggregation Inhibitors; D019787:Linoleic Acid; D001241:Aspirin
aspirin; drugs; fatty acids; lipids; pharmacology; platelets