Pharmacokinetic studies of four novel soluble epoxide hydrolase (sEH) inhibitors and anti‐inflammatory efficacy of the most promising one t‐AUCB

Abstract

Earlier sEH inhibitors such as AUDA are effective anti‐hypertensive and anti‐inflammatory agents in multiple animal models. However, their poor metabolic stability and water solubility make them difficult to use pharmacologically. For obtaining a compound easy to use in vivo, we present the PK profiles of four conformation‐restricted sEH inhibitors and anti‐inflammatory efficacy of the most promising one.Better PK parameters (higher Cmax, longer t1/2, and greater AUC) were obtained from the four tested inhibitors than AUDA with t‐AUCB showing the best result. Oral bioavailability of t‐AUCB (0.1 mg kg−1) was 75±12% (n=4). Furthermore, when mice were administrated t‐AUCB in drinking water at 4 mg L−1, a fairly stable blood concentration of ~70 nM t‐AUCB was maintained since one day administration, and was totally cleared from blood after 3 days of drug withdrawal. Finally, oral gavage of 0.5 and 1.0 mg kg−1 t‐AUCB were effectively anti‐inflammatory evidenced by reversing LPS‐induced hypotension in a dose‐dependent manner, and significantly shifting the ratio of lipid epoxides to corresponding diols in plasma. t‐AUCB appears around 10 times more orally active than AUDA in this model. Thus t‐AUCB is promising for further in vivo studies related to the biology of sEH and its potential therapeutic applications.