Pharmacokinetic optimization of four soluble epoxide hydrolase inhibitors for use in a murine model of inflammation.
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.
Liu
Jun-Yan
JY
Department of Entomology and UCD Cancer Research Center, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
Tsai
Hsing-Ju
HJ
Hwang
Sung Hee
SH
Jones
Paul D
PD
Morisseau
Christophe
C
Hammock
Bruce D
BD
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
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