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。

IF 1.4 3区 农林科学 Q2 VETERINARY SCIENCES
American journal of veterinary research Pub Date : 2025-03-21 Print Date: 2025-06-01 DOI:10.2460/ajvr.24.12.0377
Tania Perez Jimenez, Mara Trostle, Zhaohui Zhu, Stephanie Martinez, Michael H Court
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引用次数: 0

摘要

目的:探讨细胞色素(CY) P450 - 2D15 (CYP2D15)在犬右美沙芬代谢中的种群变异性。方法:从2018年至2024年从内陆太平洋西北地区招募健康宠物狗,并通过口服含有右美沙芬(一种cyp2d15特异性探针药物)的个性化药物鸡尾酒对该计划进行表型分析。给药后6小时采集经葡萄糖醛酸酶处理的尿样,检测右美沙芬和右美沙芬浓度。计算右美沙芬/右美沙芬的对数转化代谢比(DOR/DXM Log MRs)。对犬进行5种CYP2D15错义变异的基因分型。采用单变量和多变量统计方法评估DOR/ ddxm Log MRs与人口统计学变量之间的关联。结果:105只狗,包括34只混合品种和71只来自20个不同的主人指定品种的狗,被纳入并完成了研究。DOR/DXM Log MRs分布较广,在0.97 ~ 2.76之间,测井单位范围为1.8 (DOR/DXM Log MRs变化63倍)。右美沙芬除以右美沙芬的对数转化代谢率呈正态分布,呈单峰分布。DOR/ ddxm Log MR平均值(±SD)为2.04±0.37。多元线性回归分析显示,金毛DOR/ ddxm Log MRs与犬种呈显著相关(R2 = 0.16)(2.26±0.29;N = 23)和Pugs(1.47±0.29;右美沙芬除以右美沙芬的对数转化代谢比与狗的性别、年龄、体重或基因型无关。结论:DOR/DXM Log MR值在个体之间存在很大差异,这可以部分归因于品种之间的差异。临床相关性:这些发现预测了CYP2D15药物代谢的高度变异性与犬种之间的差异有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
CiteScore
1.70
自引率
10.00%
发文量
186
审稿时长
3 months
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.
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