Circumstances, Postmortem Findings, Blood Concentrations and Metabolism in a Series of Methoxyacetylfentanyl-Related Deaths

Abstract

Methoxyacetylfentanyl is one of many fentanyl analogs available as new psychoactive substances. It have been encountered in both the European Union and the United States, and existing literature suggest that methoxyacetylfentanyl is around 3 to 5-fold less potent than fentanyl. The aim of the present work was to combine case information with blood concentrations and abundance of urinary metabolites to investigate the importance of these parameters for toxicological interpretation. Quantification of methoxyacetylfentanyl in femoral blood was performed by LC-MS/MS and urinary metabolites were analyzed by LC-QTOF-MS with and without hydrolysis with β-glucuronidase/arylsulfatase. For confirmation of identified metabolites, methoxyacetylfentanyl was incubated with hepatocytes for up to 5 hours and analyzed with the same method as the urine samples. In eleven postmortem cases (27 to 41 years old and including one female) methoxyacetylfentanyl was reported in femoral blood. The cause of death was intoxication by methoxyacetylfentanyl alone or in combination with other drugs in all but one case, where death was attributed to acute complications of an underlying heart disease but with possible contribution from methoxyacetylfentanyl. In total, 27 urinary metabolites were found, including eight glucuronides. Major biotransformations were O-demethylation, dealkylation to form the nor-metabolite, mono- and dihydroxylations of the phenethyl moiety, as well as combinations thereof. The most abundant metabolites in hydrolyzed urine included O-desmethyl-, O-desmethyl-phenethyl-hydroxy-, O-desmethyl-phenethyl-hydroxymethoxy- and nor-methoxyacetylfentanyl.Differences in the abundance of methoxyacetylfentanyl and its major metabolites could be interpreted to indicate fatal intoxications in abstinent or chronic users. We postulate that urinary concentrations of methoxyacetylfentanyl and two metabolites, in combination with the methoxyacetylfentanyl concentration in femoral blood, might be good indicators of the time between administration and death as well as prior use.

Intoxications involving methoxyacetylfentanyl and U-47700: a study of 3 polydrug fatalities

“…Although lungs weighed less compared to similar cases of opioids intoxication [54], including cases #1 and #2, brain edema, and froth, a proxy for pulmonary edema, were detected.…”

Review of analytical methods for screening and quantification of fentanyl analogs and novel synthetic opioids in biological specimens

“…Extraction procedures utilized for LC–MS/MS quantitative methods are more expansive due to the applicability to multiple matrix types. While LLE [21,38,39,40,41,42,43,44,45] and SPE [23,37,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70] remain the most common techniques, PP [17,71,72,73,74,75,76,77,78,79,80,81,82], simple dilution [11,14,37,83] solvent extraction [82,84,85], SLE [86,87] and QuECHeERs [16,71,88] have been described as suitable extraction techniques among their evaluated scenarios. In some studies, sample pretreatment techniques such as PP and physical preparations (grinding [89,90], pulverization [62], and digestion [37]) were employed before extraction.…”

“…Extraction procedures utilized for LC-MS/MS quantitative methods are more expansive due to the applicability to multiple matrix types. While LLE[21,38,39,40,41,42,43,44,45] and SPE[23,37 ,46 ,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66 ,6 7,68,69,70] remain the most common techniques, PP[17,71,72,73,74,75,76,77,78,79,80,81,82], simple dilution…”

The rise and rise of fentanyl in postmortem casework

“…Publications describing methods of analysis for individual fentanyl analogs [23][24][25][26] and multiple fentanyl analogs in addition to fentanyl [27][28][29][30][31][32] all use LCMSMS and these studies provide a great starting point for laboratories introducing LCMSMS for the first time and/or developing new methods. In postmortem cases, only tissues are available due to decomposition, and there are several publications exploring the distribution of fentanyl and its analogs in different tissues including the method parameters used [13,[33][34][35][36][37].…”