LAUSR

HIGHLIGHTSWe analysed patients’ urine samples before and after the administration of 600 mg clopidogrel loading dose using 1H NMR.Multivariate analysis identified metabotypes associated with clopidogrel high on treatment platelets reactivity (HTPR).Urinary metabotypes revealed that clopidogrel HTPR is majorly associated with cardiometabolic diseases.Gut microbiota‐derived metabolites play vital role in developing clopidogrel HTPR. ABSTRACT Clopidogrel high on treatment platelets reactivity (HTPR) has burdened achieving optimum therapeutic outcome. Although there are known genetic and non‐genetic factors associated with clopidogrel HTPR, which explain in part clopidogrel HTPR, yet, great portion remains unknown, often hindering personalizing antiplatelet therapy. Nuclear magnetic resonance (1H NMR) pharmacometabolomics analysis is useful technique to phenotype drug response. We investigated using 1H NMR analysis to phenotype clopidogrel HTPR in urine. Urine samples were collected from 71 coronary artery disease (CAD) patients who were planned for interventional angiographic procedure prior to taking 600 mg clopidogrel loading dose (LD) and 6 h post LD. Patients' platelets function testing was assessed with the VerifyNow® P2Y12 assay at 6 h after LD. Urine samples were analysed using 1H NMR. Multivariate statistical analysis was used to identify metabolites associated with clopidogrel HTPR. In pre‐dose samples, 16 metabolites were associated with clopidogrel HTPR. However, 18 metabolites were associated with clopidogrel HTPR in post‐dose samples. The pathway analysis of the identified biomarkers reflected that multifactorial conditions are associated with clopidogrel HTPR. It also revealed the implicated role of gut microbiota in clopidogrel HTPR. Pharmacometabolomics not only discovered novel biomarkers of clopidogrel HTPR but also revealed implicated pathways and conditions.