title: Phenotyping drug polypharmacology via eicosanoid profiling of blood.
abstract: It is widely accepted that small-molecule drugs, despite their selectivity at primary targets, exert pharmacological effects (and safety liabilities) through a multiplicity of pathways. As such, it has proved extremely difficult to experimentally assess polypharmacology in an agnostic fashion. Profiling of metabolites produced as part of physiological responses to pharmacological stimuli provides a unique opportunity to explore drug pharmacology. A total of 122 eicosanoid lipids in human whole blood were monitored from 10 different donors upon stimulation with several inducers of immunological responses and treatment with modulators of prostaglandin (PG) and leukotriene biosynthesis, including clinical and investigational molecules. Such analysis revealed differentiation between drugs nominally targeting different eicosanoid biosynthetic enzymes, or even those designed to target the same enzyme. Profiled agents, some of them marketed products, affect eicosanoid biosynthesis in ways that cannot be predicted from information on their intended targets. As an example, we used this platform to discriminate drugs based on their ability to silence PG biosynthesis in response to bacterial lipopolysaccharide, resulting in differential pharmacological activity in an in vivo model of endotoxemia. Some of the observed effects are subject to variability among individuals, indicating a potential application of this methodology to the patient stratification, based on their responses to benchmark drugs and experimental compounds read on the eicosanome via a simple blood test.
authors.affiliation: Discovery Sciences Janssen Research & Development, LLC, San Diego, CA.
authors.forename: Jiao
authors.initials: J
authors.lastname: Song
authors.affiliation: Immunology Research Janssen Research & Development, LLC, San Diego, CA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Immunology Research Janssen Research & Development, LLC, San Diego, CA.
authors.forename: Tadimeti S
authors.initials: TS
authors.lastname: Rao
authors.affiliation: Immunology Research Janssen Research & Development, LLC, San Diego, CA.
authors.forename: Leon
authors.initials: L
authors.lastname: Chang
authors.affiliation: Skaggs School of Pharmacology and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Meehan
authors.affiliation: Discovery Sciences Janssen Research & Development, LLC, San Diego, CA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Blevitt
authors.affiliation: Discovery Sciences Janssen Research & Development, LLC, San Diego, CA.
authors.forename: Jiejun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Skaggs School of Pharmacology and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA.
authors.forename: Pieter C
authors.initials: PC
authors.lastname: Dorrestein
authors.affiliation: Discovery Sciences Janssen Research & Development, LLC, San Diego, CA.
authors.forename: Marcos E
authors.initials: ME
authors.lastname: Milla
mesh_terms: D000818:Animals; D015777:Eicosanoids / Q000097:blood*; D005260:Female; D006801:Humans; D055432:Metabolomics; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D064798:Polypharmacology; D057285:Precision Medicine
chemical_list: D015777:Eicosanoids
keywords: drug differentiation; eicosanoid biosynthesis; liquid chromatography mass spectrometry; metabolic phenotyping; patient profiling