title: 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.
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.
authors.affiliation: University of Veterinary Medicine Hannover, Institute for Food Toxicology and Analytical Chemistry, Bischofsholer Damm 15, 30173 Hannover, Germany.
authors.forename: Annika I
authors.initials: AI
authors.lastname: Ostermann
authors.affiliation: University of Veterinary Medicine Hannover, Institute for Food Toxicology and Analytical Chemistry, Bischofsholer Damm 15, 30173 Hannover, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Herbers
authors.affiliation: University of Veterinary Medicine Hannover, Institute for Food Toxicology and Analytical Chemistry, Bischofsholer Damm 15, 30173 Hannover, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Willenberg
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Rongjun
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Greite
authors.affiliation: Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Faikah
authors.initials: F
authors.lastname: Gueler
authors.affiliation: Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: 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: nils@schebb-web.de.
authors.forename: Nils Helge
authors.initials: NH
authors.lastname: Schebb
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D054883:Oxylipins / Q000378:metabolism*; D010539:Permeability; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012995:Solubility
chemical_list: C581572:1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea; D004791:Enzyme Inhibitors; D054883:Oxylipins; D010671:Phenylurea Compounds; D010880:Piperidines; D004851:Epoxide Hydrolases
keywords: Caco-2 intestinal absorption; EETs; Eicosanoids; Epoxy fatty acids; Oxylipins; Primary rat hepatocytes; Soluble epoxide hydrolase