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

A. G.P. Guedes, F. Aristizabal, A. Sole, A. Adedeji, R. Brosnan, H. Knych, J. Yang, S. H. Hwang, C. Morisseau, B. D. Hammock

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4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)230-238
Number of pages9
JournalJournal of Veterinary Pharmacology and Therapeutics
Volume41
Issue number2
DOIs
StatePublished - Apr 2018

Bibliographical note

Funding Information:
This project was supported by the Center for Equine Health (UC Davis), by NIEHS grant ES002710, NIEHS Superfund Basic Research Program grant P42 ES004699. The authors thank and would like to acknowledge Dr. Grace Monmaney, Dr. Mindy Nelson, Briana Hamamoto, Meghan Heil, Elizabeth Wofford-Richards, Thomas Bergstrom, Stacy Steinmetz, Laurie Christison, and Rahmar Oberholtzer for excellent technical assistance.

Publisher Copyright:
© 2017 John Wiley & Sons Ltd

Keywords

  • arthritis
  • fatty acid
  • lameness
  • musculoskeletal
  • pain

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