A broad-spectrum lipidomics screen of antiinflammatory drug combinations in human blood

  • Posted on: 27 August 2016
  • By: fcoldren
TitleA broad-spectrum lipidomics screen of antiinflammatory drug combinations in human blood
Publication TypeJournal Article
Year of Publication2016
AuthorsMazaleuskaya LL, Lawson JA, Li X, Grant G, Mesaros C, Grosser T, Blair IA, Ricciotti E, FitzGerald GA
JournalJCI Insight
Date Published2016 Aug 4

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.

Alternate JournalJCI Insight
PubMed ID27547824
PubMed Central IDPMC4990354
Grant ListT32 HL007971 / HL / NHLBI NIH HHS / United States
U54 HL117798 / HL / NHLBI NIH HHS / United States
UL1 TR000003 / TR / NCATS NIH HHS / United States