Hamamoto-Hardman Briana D, Steffey Eugene P, Weiner Daniel, McKemie Daniel S, Kass Philip, Knych Heather K
K.L Maddy Equine Analytical Chemistry Laboratory, School of Veterinary Medicine, University of California, Davis, California.
Department of Veterinary Surgery and Radiology, School of Veterinary Medicine, University of California, Davis, California.
J Vet Pharmacol Ther. 2019 Jul;42(4):401-410. doi: 10.1111/jvp.12759. Epub 2019 Mar 27.
The objective of the current study was to describe and characterize the pharmacokinetics and selected pharmacodynamic effects of morphine and its two major metabolites in horses following several doses of morphine. A total of ten horses were administered a single intravenous dose of morphine: 0.05, 0.1, 0.2, or 0.5 mg/kg, or saline control. Blood samples were collected up to 72 hr, analyzed for morphine, and metabolites by LC/MS/MS, and pharmacokinetic parameters were determined. Step count, heart rate and rhythm, gastrointestinal borborygmi, fecal output, packed cell volume, and total protein were also assessed. Morphine-3 glucuronide (M3G) was the predominant metabolite detected, with concentrations exceeding those of morphine-6 glucuronide (M6G) at all time points. Maximal concentrations of M3G and M6G ranged from 55.1 to 504 and 6.2 to 28.4 ng/ml, respectively, across dose groups. The initial assessment of morphine pharmacokinetics was done using noncompartmental analysis (NCA). The volume of distribution at steady-state and systemic clearance ranged from 9.40 to 16.9 L/kg and 23.3 to 32.4 ml min kg , respectively. Adverse effects included signs of decreased gastrointestinal motility and increased central nervous excitation. There was a correlation between increasing doses of morphine, increases in M3G concentrations, and adverse effects. Findings from this study support direct administration of purified M3G and M6G to horses to better characterize the pharmacokinetics of morphine and its metabolites and to assess pharmacodynamic activity of these metabolites.
本研究的目的是描述和表征多次给予吗啡后，吗啡及其两种主要代谢产物在马体内的药代动力学及选定的药效学效应。总共十匹马被静脉注射单次剂量的吗啡：0.05、0.1、0.2或0.5毫克/千克，或作为生理盐水对照。采集血样长达72小时，通过液相色谱-串联质谱法分析吗啡及其代谢产物，并确定药代动力学参数。还评估了步数、心率和心律、胃肠蠕动音、粪便产量、红细胞压积和总蛋白。吗啡-3-葡萄糖醛酸苷（M3G）是检测到的主要代谢产物，在所有时间点其浓度均超过吗啡-6-葡萄糖醛酸苷（M6G）。在各个剂量组中，M3G和M6G的最大浓度分别为55.1至504纳克/毫升和6.2至28.4纳克/毫升。吗啡药代动力学的初步评估采用非房室分析（NCA）。稳态分布容积和全身清除率分别为9.40至16.9升/千克和23.3至32.4毫升/分钟·千克。不良反应包括胃肠蠕动减弱和中枢神经兴奋增强的体征。吗啡剂量增加、M3G浓度升高与不良反应之间存在相关性。本研究结果支持直接给马施用纯化的M3G和M6G，以更好地表征吗啡及其代谢产物的药代动力学，并评估这些代谢产物的药效学活性。
