Analysis of Fentanyl and 18 Novel Fentanyl Analogs and Metabolites by LC–MS-MS, and report of Fatalities Associated with Methoxyacetylfentanyl and Cyclopropylfentanyl

Fogarty, Melissa F; Papsun, Donna M; Logan, Barry K.

doi:10.1093/jat/bky035

Cited by 110 publications

(66 citation statements)

References 8 publications

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“…In the current macaque model, a subclinical dose of radiolabeled [ 11 C]carfentanil was used to estimate RO resulting from an IM injection of naloxone. Thus, the results of this study may underestimate the dose and plasma level of NLX required to achieve a clinically significant level of RO, as very high levels of synthetic opioids have been found in overdose patients [24][25][26][27][28]. However, this study does suggest that for an invariable dose of carfentanil, increasing doses of IM NLX result in greater RO and, furthermore, increasing doses of IM NLX results in higher systemic levels.…”

Section: Discussionmentioning

confidence: 71%

The Effects of Intramuscular Naloxone Dose on Mu Receptor Displacement of Carfentanil in Rhesus Monkeys

et al. 2020

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Naloxone (NLX) is a mu receptor antagonist used to treat acute opioid overdoses. Currently approved doses of naloxone to treat opioid overdoses are 4 mg intranasal (IN) and 2 mg intramuscular (IM). However, higher mu receptor occupancy (RO) may be required to treat overdoses due to more potent synthetic opioids such as fentanyl and carfentanil that have entered the illicit drug market recently. To address this need, a higher dose of NLX has been investigated in a 5 mg IM formulation called ZIMHI but, while the effects of intravenous (IV) and IN administration of NLX on the opioid mu receptor occupancy (RO) have been studied, comparatively little is known about RO for IM administration of NLX. The goal of this study was to examine the effect of IM dosing of NLX on mu RO in rhesus macaques using [11C]carfentanil positron emission tomography (PET) imaging. The lowest dose of NLX (0.06 mg/kg) approximated 51% RO. Higher doses of NLX (0.14 mg/kg, 0.28 mg/kg) resulted in higher mu RO of 70% and 75%, respectively. Plasma levels were 4.6 ng/mL, 16.8 ng/mL, and 43.4 ng/mL for the three IM doses, and a significant correlation between percent RO and plasma NLX level was observed (r = 0.80). These results suggest that higher doses of IM NLX result in higher mu RO and could be useful in combating overdoses resulting from potent synthetic opioids.

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Section: Discussionmentioning

confidence: 71%

The Effects of Intramuscular Naloxone Dose on Mu Receptor Displacement of Carfentanil in Rhesus Monkeys

et al. 2020

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“…butyryl fentanyl/isobutyryl fentanyl and para-fluorobutyryl fentanyl/4-fluoroisobutyryl fentanyl). Another comprehensive analytical method was proposed by Fogarty et al 54 in which fentanyl and 18 novel fentanyl analogues and metabolites were evaluated in peripheral blood by LC-MS/MS. The instrumentation consisted of a Xevo TQ-S Micro coupled with an Acquity UPLC (both from Waters).…”

Section: •2 Analytical Techniquesmentioning

confidence: 99%

Ten Years of Fentanyl-like Drugs: a Technical-analytical Review

et al. 2019

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Synthetic opioids, such as fentanyl and its analogues, are a new public health warning. Clandestine laboratories produce drug analogues at a faster rate than these compounds can be controlled or scheduled by drug agencies. Detection requires specific testing and clinicians may be confronted with a sequence of severe issues concerning the diagnosis and management of these contemporary opioid overdoses. This paper deals with methods for biological sample treatment, as well as the methodologies of analysis that have been reported, in the last decade, in the field of fentanyl-like compounds. From this analysis, it emerges that the gold standard for the identification and quantification of 4-anilinopiperidines is LC-MS/MS, coupled with liquid-liquid or solid-phase extraction. In the end, the return to the scene of illicit fentanyls can be considered as a critical problem that can be tackled only with a global multidisciplinary approach.

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“…Most are based on solid phase extraction (SPE) or liquid–liquid extraction (LLE) followed by a LC–MS/MS experiment. However, these techniques have some drawbacks: they are limited by the unavailability of reference standards (RS), 11–15 and the enrichment of the library database by the addition of new multi reaction monitoring (MRM) transitions of new compounds often requires further method optimization. Moreover, targeted screening does not allow retrospective processing of MS data to identify unknown compounds.…”

Section: Introductionmentioning

confidence: 99%

Development and validation of liquid chromatography‐tandem mass spectrometry targeted screening of 16 fentanyl analogs and U‐47700 in hair: Application to 137 authentic samples

Larabi

Martin

Etting

et al. 2020

Drug Testing and Analysis

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This study was to validate a LC–MS/MS method for the determination of 17 new synthetic opioids (NSOs) in hair including 3‐fluorofentanyl, 3‐methylfentanyl, acetylfentanyl, acetylnorfentanyl, alfentanyl, butyrylfentanyl, butyrylnorfentanyl, carfentanil, fentanyl, furanylfentanyl, furanylnorfentanyl, methoxyacetylfentanyl, norcarfentanil, norfentanyl, ocfentanil, sufentanil, and U‐47700, and to apply it to 137 authentic samples. Twenty milligrams of hair was decontaminated in dichloromethane and underwent liquid extraction. 10 μL of the reconstituted residue were injected onto the system. The separation was performed in 12 minutes in a gradient mode at a flow rate of 300 μL/min using a Hypersyl Gold PFP column (100 × 2.1 mm i.d., 1.9 μm) maintained at 30°C. Compounds were detected in positive ionization and MRM modes using a TSQ Endura mass spectrometer (ThermoFisher). The method was validated according to EMA guidelines. The LLOQ was in the range 1–50 pg/mg, and the calibration ranged from the LLOQ‐1000 pg/mg. Intra‐ and inter‐day accuracy (bias) and precision were < 15%. Extraction recoveries of parent drugs and metabolites were 74–120% and 7–62%, respectively. The matrix effect was in the range 59–126% (CVs ≤ 12.9%). Fentanyl was found in six cases at concentrations of < 1–1650 pg/mg (n = 14 segments). Five fentanyl analogs were quantified in two cases: 3‐fluorofentanyl (25–150 pg/mg, n = 5), furanylfentanyl (15–500 pg/mg, n = 5), methoxyacetylfentanyl (500–600 pg/mg, n = 2), acetylfentanyl (1 pg/mg, n = 2), carfentanyl (2.5–3 pg/mg, n = 2). This fully validated method allowed us to test for the first time 3‐fluorofentanyl and norcarfentanil in hair among 15 other NSOs, and brings new data regarding 3‐fluorofentanyl and methoxyacetylfentanyl hair concentrations.

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Analysis of Fentanyl and 18 Novel Fentanyl Analogs and Metabolites by LC–MS-MS, and report of Fatalities Associated with Methoxyacetylfentanyl and Cyclopropylfentanyl

Cited by 110 publications

References 8 publications

The Effects of Intramuscular Naloxone Dose on Mu Receptor Displacement of Carfentanil in Rhesus Monkeys

The Effects of Intramuscular Naloxone Dose on Mu Receptor Displacement of Carfentanil in Rhesus Monkeys

Ten Years of Fentanyl-like Drugs: a Technical-analytical Review

Development and validation of liquid chromatography‐tandem mass spectrometry targeted screening of 16 fentanyl analogs and U‐47700 in hair: Application to 137 authentic samples

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