Pharmacokinetics and pharmacodynamics of cyclopropylfentanyl in male rats.
Pharmacokinetics and pharmacodynamics of cyclopropylfentanyl in male rats.
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DOI：
10.1007/s00213-021-05981-x
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发表时间：
2021-12
影响因子：
3.4
通讯作者：
Baumann MH
中科院分区：
文献类型：
--
作者：
Bergh MS;Bogen IL;Garibay N;Baumann MH
非法制造的芬太尼及其类似物是目前阿片类药物危机背后的主要推动力。环丙基芬太尼是一种芬太尼类似物，与许多过量死亡有关，但对其药理了解有限。在本研究中，我们建立了测定环丙基芬太尼及其主要代谢物环丙基去甲芬太尼的生物分析方法，并对其在大鼠体内的药代动力学-药效学关系进行了评价。建立了测定大鼠血浆中环丙基芬太尼和环丙基去甲芬太尼浓度的超高效液相色谱-串联质谱法(UHPLC-MS/MS)。安装有颈静脉导管和温度应答器的雄性SD大鼠皮下注射环丙基芬太尼(30,100和300gμg/kg)或生理盐水。在8小时的时间内抽取血液样本，同时测量药效终点。对分析方法进行了验证，两种分析物的定量下限都很低(15微克/毫升)。环丙基芬太尼引起热板潜伏期(ED50 = 48微克/千克)和过敏症(ED50 = 87微克/千克)的剂量相关增加，并在最高剂量下产生持久的低温。血浆环丙基芬太尼以剂量相关方式迅速升高，在15-28分钟达到最大浓度(Cmax)，而代谢物Cmax在45-90分钟出现较晚。环丙基芬太尼的Cmax值与人类非致命性中毒中测量的浓度相似；然而，母体药物：代谢物比例的差异表明新陈代谢可能存在物种间差异。我们的研究表明，环丙基芬太尼在雄性大鼠身上产生典型的阿片样作用。与吗啡相比，环丙基芬太尼的止痛效果要强得多，这表明环丙基芬太尼对不知情的使用者来说增加了过量服药的风险。
Illicitly manufactured fentanyl and its analogs are a major driving force behind the ongoing opioid crisis. Cyclopropylfentanyl is a fentanyl analog associated with many overdose deaths, but limited knowledge is available about its pharmacology. In the present study, we developed a bioanalytical method for the determination of cyclopropylfentanyl and its main metabolite cyclopropylnorfentanyl and evaluated pharmacokinetic-pharmacodynamic relationships in rats. An ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for determination of cyclopropylfentanyl and cyclopropylnorfentanyl in rat plasma. Male Sprague–Dawley rats fitted with jugular catheters and temperature transponders received cyclopropylfentanyl (30, 100, and 300 μg/kg) or saline subcutaneously. Blood specimens were withdrawn over an 8-h time period, along with measurements of pharmacodynamic endpoints. The analytical method was validated, and both analytes exhibited a low limit of quantification (15 pg/mL). Cyclopropylfentanyl caused dose-related increases in hot plate latency (ED50 = 48 µg/kg) and catalepsy (ED50 = 87 µg/kg) and produced long-lasting hypothermia at the highest dose. Plasma cyclopropylfentanyl rose rapidly in a dose-related fashion, reaching maximal concentration (Cmax) after 15–28 min, whereas metabolite Cmax occurred later at 45–90 min. Cyclopropylfentanyl Cmax values were similar to concentrations measured in non-fatal intoxications in humans; however, differences in parent drug: metabolite ratio indicated possible interspecies variance in metabolism. Our study shows that cyclopropylfentanyl produces typical opioid-like effects in male rats. Cyclopropylfentanyl displays much greater analgesic potency when compared to morphine, suggesting that cyclopropylfentanyl poses increased overdose risk for unsuspecting users.
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DOI：
10.1016/j.jpain.2010.06.011
发表时间：
2011-02
期刊：
The journal of pain
影响因子：
--
作者：
Gunn A;Bobeck EN;Weber C;Morgan MM
通讯作者：
Morgan MM
影响因子：
6.1
作者：
Astrand, Anna;Toreskog, Amanda;Vikingsson, Svante
通讯作者：
Vikingsson, Svante
影响因子：
2.5
作者：
Fagiola, Michael;Hahn, Timothy;Avella, Joseph
通讯作者：
Avella, Joseph
影响因子：
4.7
作者：
Bergh, Marianne Skov-Skov;Bogen, Inger Lise;Baumann, Michael H.
通讯作者：
Baumann, Michael H.
影响因子：
2.9
作者：
Cutler, Charlotte;Hudson, Simon
通讯作者：
Hudson, Simon