02803-MOU: Genetics of Adverse Reactions to Anesthetic and Sedative Drugs in Chow-Chows
Grant Status: Open
Moderate to severe adverse drug reactions, including unexpected effects, slow recovery, and even death have been reported following administration of anesthetic/sedative drugs by owners in some Chow Chow dog. Problematic drugs included butorphanol, acepromazine, trazodone, hydromorphone, ketamine and midazolam. In preliminary studies we have excluded a role for the MDR-1 deletion mutation found in herding dog breeds, as well as the CYP2B11/POR mutations found in sighthound breed dogs. Gene capture sequencing of DNA from representative Chow Chows identified a novel mutation in the CYP2B11 gene that is predicted to cause a damaging change in the amino acid sequence (CYP2B11-F182). This study will determine if CYP2B11-F182 mutation is responsible for decreased CYP2B11 enzyme function leading to excessive drug exposure and subsequent adverse effects in affected dogs. Previous studies have identified CYP2B11 as the primary enzyme metabolizing ketamine and midazolam. However, the identities of CYPs metabolizing the other problematic drugs are currently unknown. This study aims to ascertain the role of CYP2B 11 in metabolism of the implicated drugs, confirm the deleterious effect of the CYP2B11-Fl 82 mutation on enzyme function in vitro, determine the prevalence of the CYP2B11-F182 mutation across the Chow Chow breed, and identify other breeds with this mutation. Evidence from this study will be used to examine the effect of the CYP2B11-F182 mutation in future studies on drug pharmacokinetics and pharmacodynamics in genotyped dogs.
Funding for the research is provided through the collaborative efforts and generosity of the Chow Chow Club, Inc. The AKC Canine Health Foundation supports the funding of this effort and will oversee grant administration and scientific progress.
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