Pharmacometabolomic assessments of atenolol and hydrochlorothiazide treatment reveal novel drug response phenotypes

D. M. Rotroff, M. H. Shahin, Susan Gurley, H. Zhu, A. Motsinger-Reif, M. Meisner, A. L. Beitelshees, O. Fiehn, J. A. Johnson, M. Elbadawi-Sidhu, R. F. Frye, Y. Gong, L. Weng, R. M. Cooper-Dehoff, R. Kaddurah-Daouk

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Achieving hypertension (HTN) control and mitigating the adverse health effects associated with HTN continues to be a global challenge. Some individuals respond poorly to current HTN therapies, and mechanisms for response variation remain poorly understood. We used a nontargeted metabolomics approach (gas chromatography time-of-flight/mass spectrometry gas chromatography time-of-flight/mass spectrometry) measuring 489 metabolites to characterize metabolite signatures associated with treatment response to anti-HTN drugs, atenolol (ATEN), and hydrochlorothiazide (HCTZ), in white and black participants with uncomplicated HTN enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses study. Metabolite profiles were significantly different between races, and metabolite responses associated with home diastolic blood pressure (HDBP) response were identified. Metabolite pathway analyses identified gluconeogenesis, plasmalogen synthesis, and tryptophan metabolism increases in white participants treated with HCTZ (P < 0.05). Furthermore, we developed predictive models from metabolite signatures of HDBP treatment response (P < 1 × 10-5). As part of a quantitative systems pharmacology approach, the metabolites identified herein may serve as biomarkers for improving treatment decisions and elucidating mechanisms driving HTN treatment responses.

Original languageEnglish (US)
Pages (from-to)669-679
Number of pages11
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume4
Issue number11
DOIs
Publication statusPublished - Nov 1 2015
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Modeling and Simulation
  • Pharmacology (medical)

Cite this