Tania Perez Jimenez, Mara Trostle, Zhaohui Zhu, Stephanie Martinez, Michael H Court
{"title":"健康宠物狗的右美沙芬表型揭示了细胞色素P450 2d15介导的药物代谢的品种相关差异。","authors":"Tania Perez Jimenez, Mara Trostle, Zhaohui Zhu, Stephanie Martinez, Michael H Court","doi":"10.2460/ajvr.24.12.0377","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>To determine the population variability in dextromethorphan metabolism by cytochrome (CY) P450 2D15 (CYP2D15) in dogs.</p><p><strong>Methods: </strong>Healthy pet dogs were recruited from 2018 through 2024 from the Inland Pacific Northwest and phenotyped by orally administering the Program in Individualized Medicine cocktail, which contains dextromethorphan, a CYP2D15-specific probe drug. Glucuronidase-treated urine samples collected 6 hours after dosing were assayed for dextromethorphan and dextrorphan concentrations. Log-transformed metabolic ratios of dextrorphan divided by dextromethorphan (DOR/DXM Log MRs) were calculated. Dogs were genotyped for 5 missense CYP2D15 variants. Univariate and multivariate statistical approaches were used to evaluate associations between DOR/DXM Log MRs and demographic variables.</p><p><strong>Results: </strong>105 dogs, including 34 mixed breeds and 71 dogs from 20 different owner-designated breeds, were enrolled and completed the study. There was a wide distribution of DOR/DXM Log MRs, from 0.97 to 2.76, representing a log unit range of 1.8 (63-fold variation DOR/DXM Log MRs). Log-transformed metabolic ratios of dextrorphan divided by dextromethorphan were normally distributed and unimodal. The mean (± SD) DOR/DXM Log MR was 2.04 ± 0.37. Multiple linear regression analysis showed significant association (R2 = 0.16) between DOR/DXM Log MRs and dog breed for Golden Retrievers (2.26 ± 0.29; N = 23) and Pugs (1.47 ± 0.29; N = 3). Log-transformed metabolic ratios of dextrorphan divided by dextromethorphan were not associated with dog sex, age, weight, or genotype.</p><p><strong>Conclusions: </strong>There is substantial variability in DOR/DXM Log MR values among individuals, which can be partially attributed to differences between breeds.</p><p><strong>Clinical relevance: </strong>These findings predict high variability in the metabolism of drugs by CYP2D15 associated with differences between dog breeds.</p>","PeriodicalId":7754,"journal":{"name":"American journal of veterinary research","volume":" ","pages":""},"PeriodicalIF":1.4000,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dextromethorphan phenotyping of healthy pet dogs reveals breed-associated differences in cytochrome P450 2D15-mediated drug metabolism.\",\"authors\":\"Tania Perez Jimenez, Mara Trostle, Zhaohui Zhu, Stephanie Martinez, Michael H Court\",\"doi\":\"10.2460/ajvr.24.12.0377\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>To determine the population variability in dextromethorphan metabolism by cytochrome (CY) P450 2D15 (CYP2D15) in dogs.</p><p><strong>Methods: </strong>Healthy pet dogs were recruited from 2018 through 2024 from the Inland Pacific Northwest and phenotyped by orally administering the Program in Individualized Medicine cocktail, which contains dextromethorphan, a CYP2D15-specific probe drug. Glucuronidase-treated urine samples collected 6 hours after dosing were assayed for dextromethorphan and dextrorphan concentrations. Log-transformed metabolic ratios of dextrorphan divided by dextromethorphan (DOR/DXM Log MRs) were calculated. Dogs were genotyped for 5 missense CYP2D15 variants. Univariate and multivariate statistical approaches were used to evaluate associations between DOR/DXM Log MRs and demographic variables.</p><p><strong>Results: </strong>105 dogs, including 34 mixed breeds and 71 dogs from 20 different owner-designated breeds, were enrolled and completed the study. There was a wide distribution of DOR/DXM Log MRs, from 0.97 to 2.76, representing a log unit range of 1.8 (63-fold variation DOR/DXM Log MRs). Log-transformed metabolic ratios of dextrorphan divided by dextromethorphan were normally distributed and unimodal. The mean (± SD) DOR/DXM Log MR was 2.04 ± 0.37. Multiple linear regression analysis showed significant association (R2 = 0.16) between DOR/DXM Log MRs and dog breed for Golden Retrievers (2.26 ± 0.29; N = 23) and Pugs (1.47 ± 0.29; N = 3). Log-transformed metabolic ratios of dextrorphan divided by dextromethorphan were not associated with dog sex, age, weight, or genotype.</p><p><strong>Conclusions: </strong>There is substantial variability in DOR/DXM Log MR values among individuals, which can be partially attributed to differences between breeds.</p><p><strong>Clinical relevance: </strong>These findings predict high variability in the metabolism of drugs by CYP2D15 associated with differences between dog breeds.</p>\",\"PeriodicalId\":7754,\"journal\":{\"name\":\"American journal of veterinary research\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":1.4000,\"publicationDate\":\"2025-03-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of veterinary research\",\"FirstCategoryId\":\"97\",\"ListUrlMain\":\"https://doi.org/10.2460/ajvr.24.12.0377\",\"RegionNum\":3,\"RegionCategory\":\"农林科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/6/1 0:00:00\",\"PubModel\":\"Print\",\"JCR\":\"Q2\",\"JCRName\":\"VETERINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of veterinary research","FirstCategoryId":"97","ListUrlMain":"https://doi.org/10.2460/ajvr.24.12.0377","RegionNum":3,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/1 0:00:00","PubModel":"Print","JCR":"Q2","JCRName":"VETERINARY SCIENCES","Score":null,"Total":0}
Dextromethorphan phenotyping of healthy pet dogs reveals breed-associated differences in cytochrome P450 2D15-mediated drug metabolism.
Objective: To determine the population variability in dextromethorphan metabolism by cytochrome (CY) P450 2D15 (CYP2D15) in dogs.
Methods: Healthy pet dogs were recruited from 2018 through 2024 from the Inland Pacific Northwest and phenotyped by orally administering the Program in Individualized Medicine cocktail, which contains dextromethorphan, a CYP2D15-specific probe drug. Glucuronidase-treated urine samples collected 6 hours after dosing were assayed for dextromethorphan and dextrorphan concentrations. Log-transformed metabolic ratios of dextrorphan divided by dextromethorphan (DOR/DXM Log MRs) were calculated. Dogs were genotyped for 5 missense CYP2D15 variants. Univariate and multivariate statistical approaches were used to evaluate associations between DOR/DXM Log MRs and demographic variables.
Results: 105 dogs, including 34 mixed breeds and 71 dogs from 20 different owner-designated breeds, were enrolled and completed the study. There was a wide distribution of DOR/DXM Log MRs, from 0.97 to 2.76, representing a log unit range of 1.8 (63-fold variation DOR/DXM Log MRs). Log-transformed metabolic ratios of dextrorphan divided by dextromethorphan were normally distributed and unimodal. The mean (± SD) DOR/DXM Log MR was 2.04 ± 0.37. Multiple linear regression analysis showed significant association (R2 = 0.16) between DOR/DXM Log MRs and dog breed for Golden Retrievers (2.26 ± 0.29; N = 23) and Pugs (1.47 ± 0.29; N = 3). Log-transformed metabolic ratios of dextrorphan divided by dextromethorphan were not associated with dog sex, age, weight, or genotype.
Conclusions: There is substantial variability in DOR/DXM Log MR values among individuals, which can be partially attributed to differences between breeds.
Clinical relevance: These findings predict high variability in the metabolism of drugs by CYP2D15 associated with differences between dog breeds.
期刊介绍:
The American Journal of Veterinary Research supports the collaborative exchange of information between researchers and clinicians by publishing novel research findings that bridge the gulf between basic research and clinical practice or that help to translate laboratory research and preclinical studies to the development of clinical trials and clinical practice. The journal welcomes submission of high-quality original studies and review articles in a wide range of scientific fields, including anatomy, anesthesiology, animal welfare, behavior, epidemiology, genetics, heredity, infectious disease, molecular biology, oncology, pharmacology, pathogenic mechanisms, physiology, surgery, theriogenology, toxicology, and vaccinology. Species of interest include production animals, companion animals, equids, exotic animals, birds, reptiles, and wild and marine animals. Reports of laboratory animal studies and studies involving the use of animals as experimental models of human diseases are considered only when the study results are of demonstrable benefit to the species used in the research or to another species of veterinary interest. Other fields of interest or animals species are not necessarily excluded from consideration, but such reports must focus on novel research findings. Submitted papers must make an original and substantial contribution to the veterinary medicine knowledge base; preliminary studies are not appropriate.