Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t-TUCB in horses with experimentally induced radiocarpal synovitis.

Abstract

This study determined the pharmacokinetics, antinociceptive, and anti-inflammatory effects of the soluble epoxide hydrolase (sEH) inhibitor t-TUCB (trans-4-{4-[3-(4-Trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid) in horses with lipopolysaccharide (LPS)-induced radiocarpal synovitis. A total of seven adult healthy mares (n&#xa0;=&#xa0;4-6/treatment) were administered 3&#xa0;&#x3bc;g LPS into one radiocarpal joint and t-TUCB intravenously (i.v.) at 0 (control), 0.03, 0.1, 0.3, and 1&#xa0;mg/kg in a blinded, randomized, crossover design with at least 3&#xa0;weeks washout between. Two investigators independently assigned pain scores (at rest, walk and trot) and lameness scores before and up to 48&#xa0;hr after t-TUCB/LPS. Responses to touching the joint skin to assess tactile allodynia, plasma, and synovial fluid (SF) t-TUCB concentrations were determined before and up to 48&#xa0;hr after t-TUCB/LPS. Blood and SF were collected for clinical laboratory evaluations before and up to 48&#xa0;hr after t-TUCB/LPS. Areas under the curves of pain and lameness scores were calculated and compared between control and treatments. Data were analyzed using repeated measures ANOVA with Dunnett or Bonferroni post-test. p&#xa0;<&#xa0;.05 was considered significant. Data are mean&#xa0;&#xb1;&#xa0;SEM. Compared to control, pain, lameness, and tactile allodynia were significantly lower with 1&#xa0;mg/kg t-TUCB, but not the other doses. For 0.1, 0.3, and 1&#xa0;mg/kg t-TUCB treatments, plasma terminal half-lives were 13&#xa0;&#xb1;&#xa0;3, 13&#xa0;&#xb1;&#xa0;0.5, and 24&#xa0;&#xb1;&#xa0;5&#xa0;hr, and clearances were 68&#xa0;&#xb1;&#xa0;15, 48&#xa0;&#xb1;&#xa0;5, and 14&#xa0;&#xb1;&#xa0;1 ml&#xa0;hr&#xa0;kg. The 1 mg/kg t-TUCB reached the SF at high concentrations. There were no important anti-inflammatory effects. In conclusion, sEH inhibition with t-TUCB may provide analgesia in horses with inflammatory joint pain.