Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern

Annika I. Ostermann, Jan Herbers, Ina Willenberg, Rongjun Chen, Sung Hee Hwang, Robert Greite, Christophe Morisseau, Faikah Gueler, Bruce D. Hammock, Nils Helge Schebb

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Epoxides from polyunsaturated fatty acids (PUFAs) are potent lipid mediators. In vivo stabilization of these epoxides by blockade of the soluble epoxide hydrolase (sEH) leads to anti-inflammatory, analgesic and normotensive effects. Therefore, sEH inhibitors (sEHi) are a promising new class of drugs. Herein, we characterized pharmacokinetic (PK) and pharmacodynamic properties of a commercially available potent sEHi 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU). Cell culture studies suggest its high absorption and metabolic stability. Following administration in drinking water to rats (0.2, 1, and 5. mg TPPU/L with 0.2% PEG400), TPPU's blood concentration increased dose dependently within the treatment period to reach an almost steady state after 8 days. TPPU was found in all the tissues tested. The linoleic epoxide/diol ratios in most tissues were dose dependently increased, indicating significant sEH inhibition. Overall, administration of TPPU with the drinking water led to systemic distribution as well as high drug levels and thus makes chronic sEH inhibition studies possible.

Original languageEnglish (US)
JournalProstaglandins and Other Lipid Mediators
DOIs
StateAccepted/In press - Feb 27 2015

Keywords

  • Caco-2 intestinal absorption
  • EETs
  • Eicosanoids
  • Epoxy fatty acids
  • Oxylipins
  • Primary rat hepatocytes
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Pharmacology
  • Cell Biology

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