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

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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Liu JY,Tsai HJ,Hwang SH,Jones PD,Morisseau C,Hammock BD

doi

10.1111/j.1476-5381.2008.00009.x

subject

Has Abstract

pub_date

2009-01-01 00:00:00

pages

284-96

issue

eissn

0007-1188

issn

1476-5381

pii

BPH009

journal_volume

156

pub_type

杂志文章

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