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

Authors: Liu, JY  Tsai, HJ  Hwang, SH  Jones, PD  Morisseau, C  Hammock, BD 
Citation: Liu JY, etal., Br J Pharmacol. 2009 Jan;156(2):284-96. Epub 2009 Jan 13.
Pubmed: (View Article at PubMed) PMID:19154430
DOI: Full-text: DOI:10.1111/j.1476-5381.2008.00009.x

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.

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RGD Object Information
RGD ID: 5688360
Created: 2012-02-28
Species: All species
Last Modified: 2012-02-28
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.