Section of Anaesthesiology and Pain Therapy, Department of Clinical Veterinary Sciences, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Department of Veterinary Medical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
J Vet Pharmacol Ther. 2022 Jul;45(4):366-372. doi: 10.1111/jvp.13063. Epub 2022 Apr 29.
The goal of this study was to investigate the pharmacokinetic (PK) behaviour of dexmedetomidine in dogs administered as a pure enantiomer versus as part of a racemic mixture. Eight unmedicated intact purpose-bread beagles were included. Two intravenous treatments of either medetomidine or dexmedetomidine were administered at 10- to 14-day intervals. Atipamezole or saline solution was administered intramuscularly 45 min later. Venous blood samples were collected into EDTA collection tubes, and the quantification of dexmedetomidine and levomedetomidine was performed by chiral LC-MS/MS. All dogs appeared sedated after each treatment without complication. Plasma concentrations of levomedetomidine were measured only in the racemic group and were 51.4% (51.4%-56.1%) lower than dexmedetomidine. Non-compartmental analysis (NCA) was performed for both drugs, while dexmedetomidine data were further described using a population pharmacokinetic approach. A standard two-compartment mammillary model with linear elimination with combined additive and multiplicative error model for residual unexplained variability was established for dexmedetomidine. An exponential model was finally retained to describe inter-individual variability on parameters of clearance (Cl ) and central and peripheral volumes of distribution (V , V ). No effect of occurrence, levomedetomidine or atipamezole could be observed on dexmedetomidine PK parameters. Dexmedetomidine did not undergo significantly different PK when administered alone or as part of the racemic mixture in otherwise unmedicated dogs.
本研究旨在探讨给予犬单一对映体与外消旋混合物时，右美托咪定的药代动力学（PK）行为。纳入 8 只未用药完整的目的比格犬。以 10-14 天的间隔时间，分别进行两次静脉内给予美托咪定或右美托咪定治疗。45 分钟后，肌肉内给予阿替美唑或生理盐水。采集静脉血样至 EDTA 收集管中，通过手性 LC-MS/MS 定量检测右美托咪定和左旋美托咪定。每次治疗后，所有犬均出现镇静，无并发症。仅在消旋组中测量左旋美托咪定的血浆浓度，其水平比右美托咪定低 51.4%（51.4%-56.1%）。对两种药物均进行非房室分析（NCA），同时进一步采用群体药代动力学方法描述右美托咪定的数据。为右美托咪定建立了标准的双室乳突模型，具有线性消除，以及用于残余未解释变异性的组合加性和乘法误差模型。最终保留指数模型来描述清除率（Cl）和中央及外周分布容积（V，V）参数的个体间变异性。美托咪定的发生、左旋美托咪定或阿替美唑均不能观察到对右美托咪定 PK 参数的影响。在未用药的犬中，给予右美托咪定单药或作为外消旋混合物时，其 PK 无明显差异。
