Chromatographic separation of the isobaric compounds cyclopropylfentanyl, crotonylfentanyl, methacrylfentanyl, and para-methylacrylfentanyl for specific confirmation by LC-MS/MS

Lee, Juseon; Krotulski, Alex J; Fogarty, Melissa F; Papsun, Donna M; Logan, Barry K.

doi:10.1016/j.jchromb.2019.04.033

Cited by 13 publications

(12 citation statements)

References 20 publications

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“…To the best of our knowledge, this is the first reported UHPLC-MS/MS method established for this purpose. The method displayed an LOQ of 15 pg/mL for cyclopropylfentanyl and cyclopropylnorfentanyl, meaning a sensitivity comparable (Bergh et al 2018;Busardo et al 2019) or superior to previously reported LC-MS/MS methods for this fentanyl analog (Brockbals et al 2018;Danaceau et al 2020;Fagiola et al 2019;Fogarty et al 2018;Lee et al 2019;Maher et al 2018;Matey et al 2020;Qin et al 2019;Sofalvi et al 2019). Furthermore, the method displayed acceptable precision and accuracy, combined with no ME.…”

Section: Discussionmentioning

confidence: 69%

“…The T 1/2 of cyclopropylfentanyl in the rat was 89-115 min, which is somewhat longer than that of fentanyl (T 1/2 : 62-74 min; s.c.) (Liu 2009) and carfentanil (T 1/2 : 35-64 min; s.c.) (Bergh et al 2019a). Present knowledge about blood concentrations of cyclopropylfentanyl after human exposure originates mainly from post-mortem case work, with reported concentrations in the range of 0.80-286 ng/mL (Bergh et al 2018;Brede et al 2019;Brockbals et al 2018;Busardo et al 2019;Danaceau et al 2020;EMCDDA 2018a;Fagiola et al 2019;Fogarty et al 2018;Lee et al 2019;Maher et al 2018;Matey et al 2020). Only one study has reported circulating cyclopropylfentanyl concentrations in overdose survivors, with blood concentrations of 51 and 76 ng/mL; and these subjects were also under the influence of alcohol and/or other drugs (Müller et al 2019).…”

Section: Discussionmentioning

confidence: 99%

“…To detect such low blood concentrations of drug, highly sensitive analytical methods are required. Several targeted bioanalytical methods determining cyclopropylfentanyl in human blood samples have been developed using liquid chromatography tandem mass spectrometry (LC-MS/MS) (Adamowicz et al 2020;Bergh et al 2018;Bergh et al 2019b;Brockbals et al 2018;Busardo et al 2019;Danaceau et al 2020;Fagiola et al 2019;Fogarty et al 2018;Lee et al 2019;Maher et al 2018;Matey et al 2020;Müller et al 2019;Qin et al 2019;Sofalvi et al 2019). However, only a handful of these methods were sensitive enough to successfully detect cyclopropylfentanyl in the sub ng/mL range (< 0.100 ng/mL) (Bergh et al 2018;Busardo et al 2019;Danaceau et al 2020;Qin et al 2019), and only one method included the major metabolite cyclopropylnorfentanyl (Busardo et al 2019).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and pharmacodynamics of cyclopropylfentanyl in male rats

et al. 2021

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Background 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. 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. 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. Results 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. 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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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and pharmacodynamics of cyclopropylfentanyl in male rats

et al. 2021

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“…This can be difficult using general purpose methods on platforms such as gas chromatography mass spectrometry (GC-MS) since structurally similar compounds often have close or indistinguishable retention times and mass spectra. A number of alternative approaches to GC-MS, that can provide increased discrimination power, have been described in the literature [3][4][5] but these approaches usually require laboratories to adopt new instrumentation. Other efforts have focused on the use of existing techniques, like GC-MS, but instead leverage variations of the technique [6] which may require modification of existing instrumentation.…”

Section: Introductionmentioning

confidence: 99%

A framework for the development of targeted gas chromatography mass spectrometry (GC‐MS) methods: Synthetic cannabinoids

Sisco

Burns

Moorthy

2021

Journal of Forensic Sciences

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With the increased presence of novel psychoactive substances (NPSs) in casework, drug analysis has become more challenging. To address these challenges, new screening technologies with improved specificity are being implemented, allowing for the creation and adoption of targeted confirmatory analyses that produce more conclusive results. This paper outlines a six-step, data-driven, framework to develop and evaluate gas chromatography mass spectrometry (GC-MS) methods for targeted classes of drugs. The process emphasizes maximizing retention time differences (to minimize the potential for retention time acceptance windows to overlap) and understanding the trade-offs between sensitivity and reproducibility using a test solution containing pairs of compounds that are difficult to distinguish. The method is then evaluated by expanding the panel of compounds analyzed, identifying limitations in compound discrimination, comparing to current methods, and analyzing representative casework to establish usability. To demonstrate this framework, a method for synthetic cannabinoids was created. The developed method utilizes a DB-200 column and an isothermal temperature program. It was found that sensitivity could be adjusted, without compromising reproducibility, by altering the split ratio and injection volume. The targeted method successfully differentiated 50 cannabinoids based on either retention time differences or mass spectral dissimilarity -determined using a newly developed spectral comparison test. Compared to a general method used for casework, the targeted method was an order of magnitude more sensitive, a minute shorter, and provided major increases in retention time differences. This framework can be implemented and adapted to develop targeted methods for other applications or compound classes.

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“…The separation and identification of isomers is difficult. Some isobaric fentanyl analogues were reported to be separated by two different gradient elutions [35] or two detectors [30]. In this study, we aimed to separate as many isomers as possible under one chromatographic condition and supplement the data available on fentanyl‐related substances using high‐resolution mass spectrometry.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous separation and determination of 32 fentanyl‐related substances, including seven sets of isomeric fentanyl analogues, by ultra‐high‐performance liquid chromatography coupled with high‐resolution mass spectrometry

Zhang

Sheng

Hua

et al. 2020

J of Separation Science

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A method for separation and determination of 32 fentanyl-related substances, including seven sets of isomeric fentanyl analogues, was developed using ultrahigh-performance liquid chromatography coupled with quadrupole-orbitrap high-resolution mass spectrometry. The collision energy, chromatographic column, and mobile phase were optimized. All compounds were efficiently flushed out of a universal C18 column with a soft gradient consisting of solvent A (2 mM ammonium formate and 0.1% formic acid in water) and solvent B (2 mM ammonium formate and 0.1% formic acid in methanol) in only 20 min, achieving excellent resolution. Detection and analysis were carried out simultaneously in the positive ion mode using the full scan and data-dependent tandem mass spectrometry modes with a normalized collision energy of 40. The method was validated in terms of limit of detection, limit of quantification, linearity, accuracy, and precision. For all fentanyl-related substances, the limit of detection (0.5 ng/mL) and limit of quantification (1 ng/mL) were adequate for screening and quantification in daily drug control. Calibration curves for all compounds were established in the range of 1-500 ng/mL. The intra-and interday precision (RSD%) were within 0.4-2.3 and 0.7-2.7%, respectively. The accuracy ranged from 99 to 106%. The method was applied to analyze seized drug samples.

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Chromatographic separation of the isobaric compounds cyclopropylfentanyl, crotonylfentanyl, methacrylfentanyl, and para-methylacrylfentanyl for specific confirmation by LC-MS/MS

Cited by 13 publications

References 20 publications

Pharmacokinetics and pharmacodynamics of cyclopropylfentanyl in male rats

Pharmacokinetics and pharmacodynamics of cyclopropylfentanyl in male rats

A framework for the development of targeted gas chromatography mass spectrometry (GC‐MS) methods: Synthetic cannabinoids

Simultaneous separation and determination of 32 fentanyl‐related substances, including seven sets of isomeric fentanyl analogues, by ultra‐high‐performance liquid chromatography coupled with high‐resolution mass spectrometry

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