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Molecules (Basel, Switzerland)2021; 26(16); 5034; doi: 10.3390/molecules26165034

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

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.
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Publication Date: 2021-08-19 PubMed ID: 34443621PubMed Central: PMC8399023DOI: 10.3390/molecules26165034Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article discusses the pharmacokinetics of soluble epoxide hydrolase inhibitor, EC1728, in different species such as dogs, cats, horses, and mice after oral and intravenous drug administration. The study aims to highlight the importance of evaluating drug metabolism across different species for creating reliable and effective therapeutic options.

Introduction

  • This research study dwells on the metabolism of EC1728, a novel soluble epoxide hydrolase inhibitor, in various animal species often used as house pets.
  • The inhibitor EC1728 is being developed for pain treatment in animals.
  • The problem at hand is the lack of innovative therapeutic options for companion animals as most drugs are repurposed from those developed for humans or other diverse species.

Methodology and Results of the Study

  • The researchers investigated the pharmacokinetics (factors affecting the movement of a drug within the body), after oral and intravenous dosing of EC1728 in different species.
  • Different species showed diverse bioavailability (the extent and rate at which a drug is absorbed or becomes available at the site of physiological activity) and clearance rates.
  • Dogs and horses exhibited similar bioavailability of 42% and 50% respectively. However, mice and cats showed lower bioavailability rates of 34% and 8% respectively.
  • Cats and mice showed similar clearance rates, but clearance is over twice as fast in cats compared to dogs and horses.

Conclusion and Implications

  • Pain relief efficacy of EC1728 was confirmed in mice, dogs, and horses. Even with the rapid clearance of EC1728 in cats, it showed pain relief efficiency in an acute pain model after intravenous administration only, not oral.
  • The study concludes that the bioavailability and metabolism of a drug can vary across different species. Therefore, screening mechanisms in drug development should account for species-specific metabolism to avoid toxicity and ensure drug efficiency.
  • The importance of thorough research, taking into account the target species, is highlighted for accurate therapeutic exposures and to provide satisfactory care.

Cite This Article

APA
McReynolds CB, Yang J, Guedes A, Morisseau C, Garcia R, Knych H, Tearney C, Hamamoto B, Hwang SH, Wagner K, Hammock BD. (2021). Species Differences in Metabolism of Soluble Epoxide Hydrolase Inhibitor, EC1728, Highlight the Importance of Clinically Relevant Screening Mechanisms in Drug Development. Molecules, 26(16), 5034. https://doi.org/10.3390/molecules26165034

Publication

Molecules (Basel, Switzerland)
ISSN: 1420-3049
NlmUniqueID: 100964009
Country: Switzerland
Language: English
Volume: 26
Issue: 16
PII: 5034

Researcher Affiliations

McReynolds, Cindy B
  • UC Davis Comprehensive Cancer Center, Department of Entomology and Nematology, University of California, Davis, Davis, CA 95616, USA.
  • EicOsis, 1930 5th Street, Suite A, Davis, CA 95616, USA.
Yang, Jun
  • UC Davis Comprehensive Cancer Center, Department of Entomology and Nematology, University of California, Davis, Davis, CA 95616, USA.
  • EicOsis, 1930 5th Street, Suite A, Davis, CA 95616, USA.
Guedes, Alonso
  • Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
Morisseau, Christophe
  • UC Davis Comprehensive Cancer Center, Department of Entomology and Nematology, University of California, Davis, Davis, CA 95616, USA.
Garcia, Roberto
  • Dechra Development LLC, 1 Monument Sq, Portland, ME 04101, USA.
Knych, Heather
  • K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
  • Department of Veterinary Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
Tearney, Caitlin
  • Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
Hamamoto, Briana
  • K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
Hwang, Sung Hee
  • UC Davis Comprehensive Cancer Center, Department of Entomology and Nematology, University of California, Davis, Davis, CA 95616, USA.
  • EicOsis, 1930 5th Street, Suite A, Davis, CA 95616, USA.
Wagner, Karen
  • UC Davis Comprehensive Cancer Center, Department of Entomology and Nematology, University of California, Davis, Davis, CA 95616, USA.
  • EicOsis, 1930 5th Street, Suite A, Davis, CA 95616, USA.
Hammock, Bruce D
  • UC Davis Comprehensive Cancer Center, Department of Entomology and Nematology, University of California, Davis, Davis, CA 95616, USA.
  • EicOsis, 1930 5th Street, Suite A, Davis, CA 95616, USA.

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

Grant Funding

  • R35 ES030443 / NIH HHS
  • Every Cat Health Foundation (to A.G. for 1 mg/kg IV cat studies) / Winn Feline Foundation
  • R35 ES030443 / NIEHS NIH HHS
  • P42 ES004699 / NIEHS NIH HHS
  • T32 GM113770 / NIH HHS
  • To A.G. for dog PK studies / Center for Companion Animal Health, University of California, Davis

Conflict of Interest Statement

B.D.H., C.B.M., K.W. and J.Y. are partly employed by EicOsis, which is developing a potent soluble epoxide hydrolase inhibitor for pain relief.

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