Metabolomic profiling of metoprolol hypertension treatment reveals altered gut microbiota-derived urinary metabolites

Chad N Brocker, Thomas Velenosi, Hania K Flaten, Glenn McWilliams, Kyle McDaniel, Shelby K Shelton, Jessica Saben, Kristopher W Krausz, Frank J Gonzalez, Andrew A Monte, Chad N Brocker, Thomas Velenosi, Hania K Flaten, Glenn McWilliams, Kyle McDaniel, Shelby K Shelton, Jessica Saben, Kristopher W Krausz, Frank J Gonzalez, Andrew A Monte

Abstract

Introduction: Metoprolol succinate is a long-acting beta-blocker prescribed for the management of hypertension (HTN) and other cardiovascular diseases. Metabolomics, the study of end-stage metabolites of upstream biologic processes, yield insight into mechanisms of drug effectiveness and safety. Our aim was to determine metabolomic profiles associated with metoprolol effectiveness for the treatment of hypertension.

Methods: We performed a prospective pragmatic trial (NCT02293096) that enrolled patients between 30 and 80 years with uncontrolled HTN. Patients were started on metoprolol succinate at a dose based upon systolic blood pressure (SBP). Urine and blood pressure measurements were collected weekly. Individuals with a 10% decline in SBP or heart rate (HR) were considered responsive. Genotype for the CYP2D6 enzyme, the primary metabolic pathway for metoprolol, was evaluated for each subject. Unbiased metabolomic analyses were performed on urine samples using UPLC-QTOF mass spectrometry.

Results: Urinary metoprolol metabolite ratios are indicative of patient CYP2D6 genotypes. Patients taking metoprolol had significantly higher urinary levels of many gut microbiota-dependent metabolites including hydroxyhippuric acid, hippuric acid, and methyluric acid. Urinary metoprolol metabolite profiles of normal metabolizer (NM) patients more closely correlate to ultra-rapid metabolizer (UM) patients than NM patients. Metabolites did not predict either 10% SBP or HR decline.

Conclusion: In summary, urinary metabolites predict CYP2D6 genotype in hypertensive patients taking metoprolol. Metoprolol succinate therapy affects the microbiome-derived metabolites.

Keywords: CYP2D6; Hypertension; Lisinopril; Metabolomics; Metoprolol.

Conflict of interest statement

The authors declare no conflicts of interest. The contents of this work are the sole responsibility of the authors and do not necessarily represent the views of the National Institutes of Health (NIH).

Figures

Fig. 1
Fig. 1
Principal pathways of metoprolol metabolism. Metoprolol is primarily metabolized to α-hydroxymetoprolol (HM) and O-demethylmetoprolol (DM) by hepatic CYP2D6 and to a lesser extent CYP3A4. O-demethylmetoprolol (DM) subsequently undergoes rapid oxidation to form metoprolol acid (MA)
Fig. 2
Fig. 2
Multivariant data analysis of LC/MS-derived metabolomics data using the patient CYP2D6 phenotype. Urinary metabolomics data was subjected to unsupervised PCA-X data analysis using the patient phenotype as a classifier (a). Normal metabolizer (NM), intermediate metabolizer (IM), and ultra-rapid metabolizer (UM) phenotypes are denoted in black, red, and green, respectively. Scores scatter plot of supervised orthogonal projection to latent structure discriminant analysis (OPLS-DA) model using patient phenotype shows group clustering by phenotype (b). All data were normalized to urine creatinine abundance

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