Laboratory for Neurophysiology, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands; Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
Eur J Pharm Sci. 2017 Nov 15;109S:S132-S139. doi: 10.1016/j.ejps.2017.05.048. Epub 2017 May 27.
The pharmacokinetics and pharmacodynamics of drugs are influenced by daily fluctuations in physiological processes. The aim of this study was to determine the effect of dosing time on the pharmacokinetics and brain distribution of morphine. To this end, 4mg/kg morphine was administered intravenously to Wistar rats that were either pre-treated with vehicle or tariquidar and probenecid to inhibit processes involved in the active transport of morphine. Non-linear mixed effects modelling was used to describe the concentration-time profiles of morphine and its metabolite M3G in plasma and brain tissue. We found that the concentrations of morphine in the brain and of M3G in plasma depended on the time of day, which could be quantified by a 24-hour rhythm in the efflux of morphine from brain tissue back into the circulation, with the lowest efflux during the two light-dark phase transitions with a difference between peak and trough of 20%. The active processes involved in the clearance of morphine and its metabolite M3G from plasma also showed 24-hour variation with the highest value in the middle of the dark phase being 54% higher than the lowest value at the start of the light phase. Hence, time of day presents a considerable source of variation in the pharmacokinetics of morphine, which could be used to optimize the dosing strategy of morphine.
药物的药代动力学和药效学受到生理过程日常波动的影响。本研究旨在确定给药时间对吗啡的药代动力学和脑分布的影响。为此，将 4mg/kg 吗啡静脉注射给预先用载体或 tariquidar 和 probenecid 处理的 Wistar 大鼠，以抑制涉及吗啡主动转运的过程。非线性混合效应模型用于描述吗啡及其代谢物 M3G 在血浆和脑组织中的浓度-时间曲线。我们发现，脑组织中吗啡的浓度和血浆中 M3G 的浓度取决于一天中的时间，这可以通过 24 小时的节律来量化，即吗啡从脑组织回流到循环中的流出量最低，在两个明暗相变期间，峰值和谷值之间的差异为 20%。从血浆中清除吗啡及其代谢物 M3G 的主动过程也表现出 24 小时的变化，暗期中间的最高值比光期开始时的最低值高 54%。因此，一天中的时间是吗啡药代动力学变化的一个重要来源，可以用来优化吗啡的给药策略。
