title: Pharmacometabolomic Assessments of Atenolol and Hydrochlorothiazide Treatment Reveal Novel Drug Response Phenotypes.
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.
authors.affiliation: Department of StatisticsNorth Carolina State UniversityRaleighNorth CarolinaUSA; Bioinformatics Research CenterNorth Carolina State UniversityRaleighNorth CarolinaUSA.
authors.forename: D M
authors.initials: DM
authors.lastname: Rotroff
authors.affiliation: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida Gainesville Florida USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Shahin
authors.affiliation: Department of Medicine Duke University Medical Center and Durham Veterans Affairs Medical Center Durham North Carolina USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Gurley
authors.affiliation: Department of Psychiatry and Behavioral Sciences Duke University Durham North Carolina USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of StatisticsNorth Carolina State UniversityRaleighNorth CarolinaUSA; Bioinformatics Research CenterNorth Carolina State UniversityRaleighNorth CarolinaUSA.
authors.forename: A
authors.initials: A
authors.lastname: Motsinger-Reif
authors.affiliation: Bioinformatics Research Center North Carolina State University Raleigh North Carolina USA.
authors.forename: M
authors.initials: M
authors.lastname: Meisner
authors.affiliation: Department of Medicine University of Maryland School of Medicine Baltimore Maryland USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Beitelshees
authors.affiliation: UC Davis Genome CenterUniversity of California DavisDavisCaliforniaUSA; King Abdulaziz UniversityJeddahSaudi-Arabia.
authors.forename: O
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida Gainesville Florida USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: UC Davis Genome Center University of California Davis Davis California USA.
authors.forename: M
authors.initials: M
authors.lastname: Elbadawi-Sidhu
authors.affiliation: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida Gainesville Florida USA.
authors.forename: R F
authors.initials: RF
authors.lastname: Frye
authors.affiliation: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida Gainesville Florida USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida Gainesville Florida USA.
authors.forename: L
authors.initials: L
authors.lastname: Weng
authors.affiliation: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics University of Florida Gainesville Florida USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Cooper-DeHoff
authors.affiliation: Department of Psychiatry and Behavioral SciencesDuke UniversityDurhamNorth CarolinaUSA; Duke Institute for Brain SciencesDuke UniversityDurhamNorth CaliforniaUSA.
authors.forename: R
authors.initials: R
authors.lastname: Kaddurah-Daouk