02529: Understanding the Genetics of Adverse Drug Reactions in Sighthounds: Phase II
Grant Status: Closed
Abstract
Life-threatening unanticipated reactions to drugs with a narrow margin of safety, such as those used for anesthesia and to treat cancer, are a common yet serious concern for dog owners and veterinarians. Investigators at Washington State University have been conducting research to identify the cause of extremely slow recovery from anesthesia in a high proportion of Greyhounds, as well as in other sighthound breed dogs, including Italian Greyhounds, Scottish Deerhounds, Borzois, Irish Wolfhounds, Salukis, Afghan Hounds, and Whippets (among others). In previous work funded by the AKC Canine Health Foundation (#02242), the investigators discovered several mutations that were shown by cell-based testing to significantly decrease the function of genes responsible for breaking down (metabolizing) commonly used anesthetic drugs, as well as many other drugs used in dogs. The goal of this next phase of research is to develop a novel drug sensitivity test using saliva, blood or urine samples to identify dogs within a breed (or specific breeds) that metabolize drugs very slowly, thus creating a “personalized” or individual dog approach to drug selection. This test will then be used to confirm that the identified gene mutations are the cause of slow drug metabolism in sighthound dog breeds – as well as identify other breeds and individual dogs that could suffer from similar adverse drug reactions.
Publication(s)
Martinez, S. E., Jimenez, T. E. P., & Court, M. H. (2024). Validation of a bupropion, dextromethorphan, and omeprazole cocktail for simultaneous phenotyping of cytochrome P450 2B11, 2D15, and 3A12 activities in dogs. American Journal of Veterinary Research https://doi.org/10.2460/ajvr.24.02.0049
Martinez, S. E., Shi, J., Zhu, H.-J., Jimenez, T. E. P., Zhu, Z., & Court, M. H. (2019). Absolute quantitation of drug metabolizing cytochrome P450 enzymes and accessory proteins in dog liver microsomes using label-free standard-free analysis reveals inter-breed variability. Drug Metabolism and Disposition, dmd.119.088070. https://doi.org/10.1124/dmd.119.088070
Martinez, S. E., Andresen, M. C., Zhu, Z., Papageorgiou, I., & Court, M. H. (2020). Pharmacogenomics of poor drug metabolism in Greyhounds: Cytochrome P450 (CYP) 2B11 genetic variation, breed distribution, and functional characterization. Scientific Reports, 10(69). doi:10.1038/s41598-019-56660-z
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