title: A broad-spectrum lipidomics screen of antiinflammatory drug combinations in human blood.
abstract: Current methods of drug screening in human blood focus on the immediate products of the affected pathway and mostly rely on approaches that lack sensitivity and the capacity for multiplex analysis. We have developed a sensitive and selective method based on ultra-performance liquid chromatography-tandem mass spectrometry to scan the effect of drugs on the bioactive eicosanoid lipidome in vitro and ex vivo. Using small sample sizes, we can reproducibly measure a broad spectrum of eicosanoids in human blood and capture drug-induced substrate rediversion and unexpected shifts in product formation. Microsomal prostaglandin E synthase-1 (mPGES-1) is an antiinflammatory drug target alternative to COX-1/-2. Contrasting effects of targeting mPGES-1 versus COX-1/-2, due to differential substrate shifts across the lipidome, were observed and can be used to rationalize and evaluate drug combinations. Finally, the in vitro results were extrapolated to ex vivo studies by administration of the COX-2 inhibitor, celecoxib, to volunteers, illustrating how this approach can be used to integrate preclinical and clinical studies during drug development.
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Liudmila L
authors.initials: LL
authors.lastname: Mazaleuskaya
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Lawson
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Xuanwen
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Grant
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Clementina
authors.initials: C
authors.lastname: Mesaros
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Tilo
authors.initials: T
authors.lastname: Grosser
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ricciotti
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald