2. Academic Validation
  3. 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

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

  • Prostaglandins Other Lipid Mediat. 2015 Sep;121(Pt A):131-7. doi: 10.1016/j.prostaglandins.2015.06.005.
Annika I Ostermann 1,  Jan Herbers 1,  Ina Willenberg 1,  Rongjun Chen 2,  Sung Hee Hwang 3,  Robert Greite 2,  Christophe Morisseau 3,  Faikah Gueler 2,  Bruce D Hammock 3,  Nils Helge Schebb 4
Affiliations

Affiliations

  • 1 University of Veterinary Medicine Hannover, Institute for Food Toxicology and Analytical Chemistry, Bischofsholer Damm 15, 30173 Hannover, Germany.
  • 2 Department of Nephrology, Hannover Medical School, Hannover, Germany.
  • 3 Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
  • 4 University of Veterinary Medicine Hannover, Institute for Food Toxicology and Analytical Chemistry, Bischofsholer Damm 15, 30173 Hannover, Germany; University of Wuppertal, Institute of Food Chemistry, Wuppertal, Germany. Electronic address: [email protected].
PMID: 26117215 DOI: 10.1016/j.prostaglandins.2015.06.005
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 5mg 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.

Keywords

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

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