Department of Circulation and Medical Imaging, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
Clinic of Emergency Medicine and Prehospital Care, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
Eur J Clin Pharmacol. 2021 Dec;77(12):1901-1908. doi: 10.1007/s00228-021-03190-1. Epub 2021 Jul 29.
Remifentanil has been shown to increase the bioavailability of nasally administered naloxone. The aim of this study was to explore the nature of this observation.
We analysed samples from three pharmacokinetic studies to determine the serum concentrations of naloxone-3-glucuronide (N3G), the main metabolite of naloxone, with or without exposure to remifentanil. To enable direct comparison of the three studies, the data are presented as metabolic ratios (ratio of metabolite to mother substance, N3G/naloxone) and dose-corrected values of the area under the curve and maximum concentration (Cmax).
Under remifentanil exposure, the time to maximum concentration (Tmax) for N3G was significantly higher for intranasal administration of 71 min compared to intramuscular administration of 40 min. The dose-corrected Cmax of N3G after intranasal administration of naloxone under remifentanil exposure was significantly lower (4.5 ng/mL) than in subjects not exposed to remifentanil (7.8-8.4 ng/mL). The metabolic ratios after intranasal administration rose quickly after 30-90 min and were 2-3 times higher at 360 min compared to intravenous and intramuscular administration. Remifentanil exposure resulted in a much slower increase of the N3G/naloxone ratio after intranasal administration compared to intranasal administration with the absence of remifentanil. After remifentanil infusion was discontinued, this effect gradually diminished. From 240 min there was no significant difference between the ratios observed after intranasal naloxone administration.
Remifentanil increases the bioavailability of naloxone after nasal administration by reducing the pre-systemic metabolism of the swallowed part of the nasal dose.
已有研究表明，瑞芬太尼可提高鼻内给予纳洛酮的生物利用度。本研究旨在探讨这一观察结果的本质。
我们分析了三项药代动力学研究的样本，以确定纳洛酮-3-葡萄糖醛酸（N3G）的血清浓度，这是纳洛酮的主要代谢物，有无瑞芬太尼暴露。为了能够直接比较这三项研究，数据以代谢比（代谢物与母体物质之比，N3G/纳洛酮）和曲线下面积和最大浓度（Cmax）的剂量校正值呈现。
在瑞芬太尼暴露下，N3G 的达峰时间（Tmax）经鼻给药时明显高于肌内给药的 40 分钟，为 71 分钟。在瑞芬太尼暴露下经鼻给予纳洛酮时，N3G 的剂量校正 Cmax 明显较低（4.5ng/mL），而在未暴露于瑞芬太尼的受试者中，Cmax 为 7.8-8.4ng/mL。在瑞芬太尼暴露下，经鼻给予纳洛酮后，代谢比在 30-90 分钟内迅速上升，在 360 分钟时比静脉和肌内给药时高 2-3 倍。与无瑞芬太尼存在时的经鼻给药相比，瑞芬太尼暴露后，经鼻给予纳洛酮时 N3G/纳洛酮的比值增加速度明显较慢。停止瑞芬太尼输注后，这种影响逐渐减弱。从 240 分钟开始，经鼻给予纳洛酮后观察到的比值之间没有显著差异。
瑞芬太尼通过减少鼻内给药吞咽部分的首过代谢，增加了鼻内给予纳洛酮的生物利用度。
