Pharmacometabolomics Enables Real-World Drug Metabolism Sciences

Background/Objectives: Pharmacogenomics (PGx) has revolutionized personalized medicine, notably by predicting drug responses through the study of the metabolic genotype of drug-metabolizing enzymes. However, these genotypes rely heavily on the availability and completeness of drug metabolism information and do not account for (all) "phenoconversion" factors, like drug-drug interactions and comorbidities. To address these limitations, a more phenotypic approach would be desirable, for which pharmacometabolomics (PMx) could be useful by studying and elucidating drug metabolism in patient samples, such as blood and urine. Methods: This study explored the potential of PMx to analyze real-world drug metabolite profiles of the extensively studied drug cyclosporine (CsA) using 24-h urine samples from 732 kidney and 350 liver transplant recipients included in the TransplantLines Biobank and Cohort Study (NCT identifier NCT03272841). Detected metabolites were matched with existing information on CsA metabolism gathered through a comprehensive literature review, aiming to confirm previously reported metabolites and identify potentially unreported ones. Results: Our analyses confirmed the urinary presence of CsA and six known metabolites. Additionally, we detected three known metabolites not previously reported in urine and identified one unreported metabolite, potentially suggesting the involvement of glutathione conjugation. Lastly, the observed metabolic patterns showed no notable differences between kidney and liver transplant recipients. Conclusions: Our findings demonstrate the potential of PMx to enhance the understanding of drug metabolism, even for well-studied compounds such as CsA. Moreover, this study highlights the value of PMx in real-world drug metabolism research and its potential to complement PGx in advancing personalized medicine.