Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats
Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats
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DOI：
10.1016/j.neuropharm.2019.04.002
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发表时间：
2019-11-01
影响因子：
4.7
通讯作者：
Baumann, Michael H.
中科院分区：
文献类型：
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作者：
Bergh, Marianne Skov-Skov;Bogen, Inger Lise;Baumann, Michael H.
非法制造的芬太尼及其类似物加剧了目前的阿片类药物过量危机。卡芬太尼是一种芬太尼类似物，其效力是吗啡的1万倍，但有关其药理的信息有限。本研究有两个目的：1)验证卡芬太尼及其代谢产物去甲卡芬太尼在小体积样品中的定量方法；2)用该方法研究大鼠体内的药效学-药动学关系。该分析方法包括血浆样品的液-液萃取，然后使用超高效液相色谱-串联质谱仪(UHPLC-MS/MS)对卡芬太尼和去甲卡芬太尼进行定量。该方法按照SWGTOX指南进行验证，两种分析物的检出限和定量限分别为7.5和15pg/mL。安装颈静脉导管和体温应答器的雄性SD大鼠皮下注射卡芬太尼(1、3和10mU g/kg)或生理盐水。重复采集血样超过8小时，并进行药效学测量，包括核心体温和嗜睡评分。卡芬太尼可引起持续8h的剂量相关的体温降低和嗜睡，卡芬太尼的C-max出现在15min，而代谢物C(Max)出现在1-2 h，两种分析物的浓度均随剂量增加而升高，但曲线下面积值在10µg/kg后明显大于预期。卡芬太尼的血浆半衰期随剂量增加而延长。我们的研究结果表明，卡芬太尼会产生明显的体温过低和过敏症，并伴随着药物在高剂量下的非线性累积。我们推测，卡芬太尼在人体内的清除障碍可能会导致这种超强阿片激动剂的威胁生命的效果。本文是题为《阿片类药物药理学的新前景》特刊的一部分。
The current opioid overdose crisis is being exacerbated by illicitly manufactured fentanyl and its analogs. Carfentanil is a fentanyl analog that is 10,000-times more potent than morphine, but limited information is available about its pharmacology. The present study had two aims: 1) to validate a method for quantifying carfentanil and its metabolite norcarfentanil in small-volume samples, and 2) to use the method for examining pharmacodynamic-pharmacokinetic relationships in rats. The analytical method involved liquid-liquid extraction of plasma samples followed by quantitation of carfentanil and norcarfentanil using ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). The method was validated following SWGTOX guidelines, and both analytes displayed limits of detection and quantification at 7.5 and 15 pg/mL, respectively. Male Sprague-Dawley rats fitted with jugular catheters and temperature transponders received subcutaneous carfentanil (1, 3 and 10 mu g/kg) or saline. Repeated blood specimens were obtained over 8 h, along with pharmacodynamic measures including core temperature and catalepsy scores. Carfentanil produced dose-related hypothermia and catalepsy that lasted up to 8 h. Carfentanil C-max occurred at 15 min whereas metabolite C(max )was at 1-2 h. Concentrations of both analytes increased in a dose-related fashion, but area-under-the-curve values were much greater than predicted after 10 mu g/kg. Plasma half-life for carfentanil increased at higher doses. Our findings reveal that carfentanil produces marked hypothermia and catalepsy, which is accompanied by nonlinear accumulation of the drug at high doses. We hypothesize that impaired clearance of carfentanil in humans could contribute to life-threatening effects of this ultrapotent opioid agonist.This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.