Title: Species Differences in Metabolism of Soluble Epoxide Hydrolase Inhibitor, EC1728, Highlight the Importance of Clinically Relevant Screening Mechanisms in Drug Development.

Authors: McReynolds, Cindy B; Yang, Jun; Guedes, Alonso; Morisseau, Christophe; Garcia, Roberto; Knych, Heather; Tearney, Caitlin; Hamamoto, Briana; Hwang, Sung Hee; Wagner, Karen; Hammock, Bruce D

Published In Molecules, (2021 Aug 19)

Abstract: There are few novel therapeutic options available for companion animals, and medications rely heavily on repurposed drugs developed for other species. Considering the diversity of species and breeds in companion animal medicine, comprehensive PK exposures in the companion animal patient is often lacking. The purpose of this paper was to assess the pharmacokinetics after oral and intravenous dosing in domesticated animal species (dogs, cats, and horses) of a novel soluble epoxide hydrolase inhibitor, EC1728, being developed for the treatment of pain in animals. Results: Intravenous and oral administration revealed that bioavailability was similar for dogs, and horses (42 and 50% F) but lower in mice and cats (34 and 8%, respectively). Additionally, clearance was similar between cats and mice, but >2× faster in cats vs. dogs and horses. Efficacy with EC1728 has been demonstrated in mice, dogs, and horses, and despite the rapid clearance of EC1728 in cats, analgesic efficacy was demonstrated in an acute pain model after intravenous but not oral dosing. Conclusion: These results demonstrate that exposures across species can vary, and investigation of therapeutic exposures in target species is needed to provide adequate care that addresses efficacy and avoids toxicity.

PubMed ID: 34443621

MeSH Terms: Animals; Biological Availability; Cats; Dogs; Drug Development*; Enzyme Inhibitors/metabolism*; Enzyme Inhibitors/pharmacokinetics; Enzyme Inhibitors/pharmacology; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/chemistry; Horses; Mice; Solubility; Species Specificity