Pharmacokinetic optimization of four soluble epoxide hydrolase inhibitors for use in a murine model of inflammation

Jun Yan Liu, Hsing Ju Tsai, Sung Hee Hwang, Paul D. Jones, Christophe Morisseau, Bruce D. Hammock

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Background and purpose: 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. Experimental approach: 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. Key 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 and implications: 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. Mandarin translation of abstract.

Original languageEnglish (US)
Pages (from-to)284-296
Number of pages13
JournalBritish Journal of Pharmacology
Volume156
Issue number2
DOIs
StatePublished - Jan 2009

Keywords

  • Bioavailability
  • Efficacy
  • LC-MS/MS
  • LPS
  • Murine
  • Oxylipin mediators
  • Pharmacokinetics
  • SEH inhibitor

ASJC Scopus subject areas

  • Pharmacology

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