title: Pharmacokinetics and in vivo potency of soluble epoxide hydrolase inhibitors in cynomolgus monkeys.
abstract: OBJECTIVE
  Soluble epoxide hydrolase inhibitors (sEHIs) possess anti-inflammatory, antiatherosclerotic, antihypertensive and analgesic properties. The pharmacokinetics (PK) and pharmacodynamics in terms of inhibitory potency of sEHIs were assessed in non-human primates (NHPs). Development of a sEHI for use in NHPs will facilitate investigations on the role of sEH in numerous chronic inflammatory conditions.
  
  
  METHODS
  PK parameters of 11 sEHIs in cynomolgus monkeys were determined after oral dosing with 0.3 mg·kg(-1). Their physical properties and inhibitory potency in hepatic cytosol of cynomolgus monkeys were examined. Dose-dependent effects of the two inhibitors 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) and the related acetyl piperidine derivative, 1-trifluoromethoxyphenyl-3-(1-acetylpiperidin-4-yl) urea (TPAU), on natural blood eicosanoids, were determined.
  
  
  RESULTS
  Among the inhibitors tested, TPPU and two 4-(cyclohexyloxy) benzoic acid urea sEHIs displayed high plasma concentrations (>10 × IC(50)), when dosed orally at 0.3 mg·kg(-1). Although the 4-(cyclohexyloxy) benzoic acid ureas were more potent against monkey sEH than piperidyl ureas (TPAU and TPPU), the latter compounds showed higher plasma concentrations and more drug-like properties. The C(max) increased with dose from 0.3 to 3 mg·kg(-1) for TPPU and from 0.1 to 3 mg·kg(-1) for TPAU, although it was not linear over this range of doses. As an indication of target engagement, ratios of linoleate epoxides to diols increased with TPPU administration.
  
  
  CONCLUSIONS
  Our data indicate that TPPU is suitable for investigating sEH biology and the role of epoxide-containing lipids in modulating inflammatory diseases in NHPs.
authors: Department of Entomology and Cancer Center, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
authors: A
authors: A
authors: Ulu
authors: Se
authors: S
authors: Appt
authors: C
authors: C
authors: Morisseau
authors: S H
authors: SH
authors: Hwang
authors: P D
authors: PD
authors: Jones
authors: T E
authors: TE
authors: Rose
authors: H
authors: H
authors: Dong
authors: J
authors: J
authors: Lango
authors: J
authors: J
authors: Yang
authors: H J
authors: HJ
authors: Tsai
authors: C
authors: C
authors: Miyabe
authors: C
authors: C
authors: Fortenbach
authors: M R
authors: MR
authors: Adams
authors: B D
authors: BD
authors: Hammock
mesh_terms: D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008252:Macaca fascicularis; D010671:Phenylurea Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C577028:1-trifluoromethoxyphenyl-3-(1-acetylpiperidin-4-yl)urea; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D010880:Piperidines; D014508:Urea; D004851:Epoxide Hydrolases