Abstract
BackgroundIllicitly 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.MethodAn 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 Blood specimens were withdrawn over an 8-h time period, along with measurements of pharmacodynamic endpoints.ResultsThe analytical method was validated, and both analytes exhibited a low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.ConclusionOur 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.
Highlights
IntroductionSince 2013, there has been a surge in the number of overdose deaths related to the synthetic opioid fentanyl and its many analogs (Jannetto et al 2019; O’Donnell et al 2020)
Since 2013, there has been a surge in the number of overdose deaths related to the synthetic opioid fentanyl and its many analogs (Jannetto et al 2019; O’Donnell et al 2020).Cyclopropylfentanyl is a highly potent and dangerous fentanyl analog which has been detected in powders resembling heroin, as well as in liquids and counterfeit prescription drugs (DEA 2017; EMCDDA 2018a)
Cyclopropylfentanyl is a recently encountered clandestine fentanyl analog associated with a high number of overdose deaths (EMCDDA 2018a; O’Donnell et al 2020), but limited data is available about its pharmacokinetics and pharmacodynamic effects
Summary
Since 2013, there has been a surge in the number of overdose deaths related to the synthetic opioid fentanyl and its many analogs (Jannetto et al 2019; O’Donnell et al 2020). Cyclopropylfentanyl is a highly potent and dangerous fentanyl analog (see Fig. 1) which has been detected in powders resembling heroin, as well as in liquids and counterfeit prescription drugs (DEA 2017; EMCDDA 2018a). Cyclopropylfentanyl is a fentanyl analog associated with many overdose deaths, but limited knowledge is available about its pharmacology. We developed a bioanalytical method for the determination of cyclopropylfentanyl and its main metabolite cyclopropylnorfentanyl and evaluated pharmacokinetic-pharmacodynamic relationships in rats. Method 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. Conclusion 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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