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 = 4-6/treatment) were administered 3 μg LPS into one radiocarpal joint and t-TUCB intravenously (i.v.) at 0 (control), 0.03, 0.1, 0.3, and 1 mg/kg in a blinded, randomized, crossover design with at least 3 weeks washout between. Two investigators independently assigned pain scores (at rest, walk and trot) and lameness scores before and up to 48 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 hr after t-TUCB/LPS. Blood and SF were collected for clinical laboratory evaluations before and up to 48 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 < .05 was considered significant. Data are mean ± SEM. Compared to control, pain, lameness, and tactile allodynia were significantly lower with 1 mg/kg t-TUCB, but not the other doses. For 0.1, 0.3, and 1 mg/kg t-TUCB treatments, plasma terminal half-lives were 13 ± 3, 13 ± 0.5, and 24 ± 5 hr, and clearances were 68 ± 15, 48 ± 5, and 14 ± 1 ml hr-1  kg-1 . 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.

• Authors: A G P Guedes, F Aristizabal, A Sole, A Adedeji, R Brosnan, H Knych, J Yang, S-H Hwang, C Morisseau, B D Hammock
• Journal: Journal of veterinary pharmacology and therapeutics (J Vet Pharmacol Ther) Vol. 41 Issue 2 Pg. 230-238 (Apr 2018) ISSN: 1365-2885 [Electronic] England
• PMID: 29067696 (Publication Type: Journal Article, Randomized Controlled Trial)
• Copyright: © 2017 John Wiley & Sons Ltd.

Chemical References

• 4-(4-(3-(4-trifluoromethoxy-phenyl)ureido)cyclohexyloxy)benzoic acid
• Analgesics
• Benzoates
• Phenylurea Compounds
• Epoxide Hydrolases

Topics

• Analgesics (pharmacokinetics, pharmacology)
• Animals
• Benzoates (pharmacokinetics, pharmacology)
• Carpus, Animal
• Cross-Over Studies
• Epoxide Hydrolases (antagonists & inhibitors)
• Female
• Horse Diseases (drug therapy)
• Horses
• Joint Diseases (drug therapy, veterinary)
• Lameness, Animal (drug therapy, etiology)
• Phenylurea Compounds (pharmacokinetics, pharmacology)
• Synovitis (drug therapy, veterinary)