title: Pharmacokinetic optimization of four soluble epoxide hydrolase inhibitors for use in a murine model of inflammation.
abstract: OBJECTIVE
  Early soluble epoxide hydrolase inhibitors (sEHIs) such as 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) are effective anti-hypertensive and anti-inflammatory agents in various animal models. However, their poor metabolic stability and limited water solubility make them difficult to use pharmacologically. Here we present the evaluation of four sEHIs for improved pharmacokinetic properties and the anti-inflammatory effects of one sEHI.
  
  
  METHODS
  The pharmacokinetic profiles of inhibitors were determined following p.o. (oral) administration and serial bleeding in mice. Subsequently the pharmacokinetics of trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), the most promising inhibitor, was further studied following s.c. (subcutaneous), i.v. (intravenous) injections and administration in drinking water. Finally, the anti-inflammatory effect of t-AUCB was evaluated by using a lipopolysaccharide (LPS)-treated murine model.
  
  
  RESULTS
  Better pharmacokinetic parameters (higher C(max), longer t(1/2) and greater AUC) were obtained from the tested inhibitors, compared with AUDA. Oral bioavailability of t-AUCB (0.1 mg.kg(-1)) was 68 +/- 22% (n = 4), and giving t-AUCB in drinking water is recommended as a feasible, effective and easy route of administration for chronic studies. Finally, t-AUCB (p.o.) reversed the decrease in plasma ratio of lipid epoxides to corresponding diols (a biomarker of soluble epoxide hydrolase inhibition) in lipopolysaccharide-treated mice. The in vivo potency of 1 mg.kg(-1) of t-AUCB (p.o.) was better in this inflammatory model than that of 10 mg.kg(-1) of AUDA-butyl ester (p.o) at 6 h after treatment.
  
  
  CONCLUSIONS
  t-AUCB is a potent sEHI with improved pharmacokinetic properties. This compound will be a useful tool for pharmacological research and a promising starting point for drug development.
authors.affiliation: Department of Entomology and UCD Cancer Research Center, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Jun-Yan
authors.initials: JY
authors.lastname: Liu
authors.forename: Hsing-Ju
authors.initials: HJ
authors.lastname: Tsai
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Paul D
authors.initials: PD
authors.lastname: Jones
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D012995:Solubility; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D008070:Lipopolysaccharides; D014508:Urea; D004851:Epoxide Hydrolases