Impact of environmentally induced hypothermia on fentanyl and norfentanyl pharmacokinetics following intravenous administration to Wistar rats.

IF 3.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pharmacological Reports Pub Date : 2026-04-01 Epub Date: 2026-01-23 DOI:10.1007/s43440-026-00826-w

Paulina Stach, Kamil Skowron, Sebastian Rojek, Agnieszka Cios, Anna Wesołowska, Marilyn A Huestis, Krzysztof Gil

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引用次数: 0

Abstract

Background: Fentanyl, a synthetic opioid with potent analgesic and sedative properties, is widely administered in intensive care. Many critically ill patients present with, or develop, hypothermia driven by multifactorial disturbances such as sepsis, trauma, circulatory shock, or environmental exposure. Because reduced core temperature affects perfusion, metabolism, and clearance, hypothermia may meaningfully alter fentanyl disposition, although these effects remain insufficiently defined. Given these uncertainties, this study investigates how moderate hypothermia (MH) and severe hypothermia (SH) alter the pharmacokinetics of fentanyl and its primary metabolite, norfentanyl, compared with normothermic controls.

Methods: Male Wistar rats were divided into three groups and subjected to different environmental temperatures: normothermic controls (37 °C), MH (30 °C), and SH (27 °C). Fentanyl (10 µg/kg) was administered via a short intravenous infusion, and serial blood samples were collected over 60 min. Serum fentanyl and norfentanyl concentrations were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Pharmacokinetic parameters were calculated using Phoenix WinNonlin software.

Results: Maximum fentanyl concentration increased in both MH and SH groups, reaching statistical significance only under severe hypothermia (p < 0.001). The area under the concentration-time curve (AUC) increased markedly (p = 0.009) in SH group, indicating increased overall drug exposure. Clearance decreased by 44% (p = 0.010), and volume of distribution in steady state (V_ss) was reduced in both groups (SH: p < 0.001, MH: p = 0.029), reflecting impaired drug elimination under severe hypothermic conditions. For norfentanyl, exposure increased significantly in the SH group across all parameters, whereas in the MH group increases were limited to C_max and AUC_0-t.

Conclusions: Hypothermia significantly alters fentanyl and norfentanyl pharmacokinetics in a temperature-dependent manner.

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环境诱导的低温对Wistar大鼠静脉注射芬太尼和去芬太尼药代动力学的影响。

背景：芬太尼是一种具有强效镇痛和镇静作用的合成阿片类药物，广泛应用于重症监护。许多危重病人由于脓毒症、创伤、循环性休克或环境暴露等多因素干扰而出现或发展为低温症。由于降低的核心温度影响灌注、代谢和清除，低体温可能会有意地改变芬太尼的处置，尽管这些影响仍然没有充分的定义。考虑到这些不确定性，本研究调查了与常温对照相比，中度低温（MH）和重度低温（SH）如何改变芬太尼及其主要代谢物——去芬太尼的药代动力学。方法：雄性Wistar大鼠分为常温（37°C）、MH（30°C）、SH（27°C）三组。短时间静脉输注芬太尼（10µg/kg），并在60 min内连续采集血样。采用液相色谱-电喷雾电离-串联质谱法（LC-ESI-MS/MS）测定血清芬太尼和去芬太尼浓度。采用Phoenix WinNonlin软件计算药动学参数。结果：MH组和SH组最大芬太尼浓度均升高，只有在严重低温下（p ss）两组最大芬太尼浓度（SH: p max和AUC0-t）均降低，差异有统计学意义。结论：低温显著改变芬太尼和去芬太尼的药代动力学，并呈温度依赖性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmacological Reports 医学-药学

CiteScore

8.40

自引率

0.00%

发文量

审稿时长

6 months

期刊介绍： Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures. Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology. Studies of plant extracts are not suitable for Pharmacological Reports.