目的:使用肝脏P450酶CYP2B11,CYP2D15和CYP3A12的特定底物,为狗开发细胞色素P450(CYP)表型鉴定混合物,并确定是否可以使用替代采样方法(唾液和尿液)或单个时间点采样代替多次血液采样。
方法:从2019年2月至2019年5月,12只健康的客户拥有的狗(8只雌性和4只雄性)。
方法:在一项随机交叉研究中,狗接受口服探针药物安非他酮(75毫克),右美沙芬(30毫克),或单独使用奥美拉唑(40mg)或作为3种药物组合(个体化医学计划[PrIMe]鸡尾酒),以评估CYP2B11,CYP2D15和CYP3A12的同时表型。使用血浆测定探针药物和代谢物的药代动力学概况,唾液,还有尿液.狗单独或联合接受探针药物。使用血浆测定探针药物和代谢物给药后6小时的药代动力学曲线,唾液,还有尿液.
结果:PrIMe鸡尾酒耐受性良好。当一起施用时,探针药物之间没有统计学上显著的相互作用。所有探针药物在给药后4小时的单个时间点血浆代谢比与血浆浓度-时间曲线(AUC)比下的相应面积密切相关。CYP3A12和CYP2D15的唾液AUC代谢比以及CYP2B11和CYP2D15的6小时尿与血浆AUC比相关。
结论:使用血浆4小时单时间点样品代谢比,PrIMe混合物可用于同时进行CYP表型分析。唾液和尿液采样适用于特定的CYP。
结论:PrIMe鸡尾酒有潜力作为一种有用的工具在狗中检测临床上重要的CYP介导的药物-药物相互作用,鉴定新的药物源,确定单个狗的药物代谢表型,有助于个性化的剂量选择,并评价各种生理状态对药物代谢的影响。
OBJECTIVE: Develop a cytochrome P450 (CYP) phenotyping cocktail for dogs using specific substrates for hepatic P450 enzymes CYP2B11, CYP2D15, and CYP3A12 and determine whether alternative sampling methods (saliva and urine) or single time point samples could be used instead of multiple blood sampling.
METHODS: 12 healthy client-owned dogs (8 females and 4 males) from February 2019 to May 2019.
METHODS: In a randomized crossover study, dogs received oral administration of the probe drug bupropion (75 mg), dextromethorphan (30 mg), or omeprazole (40 mg) alone or as a 3-drug combination (Program in Individualized Medicine [PrIMe] cocktail) to evaluate simultaneous phenotyping of CYP2B11, CYP2D15, and CYP3A12. Pharmacokinetic profiles for the probe drugs and metabolites were determined using plasma, saliva, and urine. Dogs received probe drugs alone or combined. Pharmacokinetic profiles up to 6 hours postdose for the probe drugs and metabolites were determined using plasma, saliva, and urine.
RESULTS: The PrIMe cocktail was well tolerated. There was no statistically significant interaction between the probe drugs when administered together. Single time point plasma metabolic ratios at 4 hours postdose for all probe drugs strongly correlated with the corresponding area under the plasma concentration-versus-time curve (AUC) ratios. Saliva AUC metabolic ratios for CYP3A12 and CYP2D15 and 6-hour urine for CYP2B11 and CYP2D15 were correlated with plasma AUC ratios.
CONCLUSIONS: The PrIMe cocktail can be used for simultaneous CYP phenotyping using plasma 4-hour single time point sample metabolic ratios. Saliva and urine sampling are suitable for specific CYPs.
CONCLUSIONS: The PrIMe cocktail has potential as a useful tool in dogs to detect clinically important CYP-mediated drug-drug interactions, identify novel pharmacogenes, determine the drug-metabolizing phenotype of individual dogs, aid in individualized dose selection, and evaluate the effects of various physiological states on drug metabolism.