scholarly journals Structure Elucidation of Urinary Metabolites of Fentanyl and Five Fentanyl Analogs using LC-QTOF-MS, Hepatocyte Incubations and Synthesized Reference Standards

2020 ◽  
Author(s):  
Jakob Wallgren ◽  
Svante Vikingsson ◽  
Tobias Rautio ◽  
Enas Nasr ◽  
Anna Åstrand ◽  
...  
Keyword(s):  
Urinary Metabolites ◽  
Reference Standards ◽  
Urine Samples ◽  
Data Sets ◽  
Hydroxylated Metabolites ◽  
Flight Mass Spectrometry ◽  
Starting Point ◽  
Fentanyl Analogs ◽  
Hydroxylated Metabolite

Abstract Fentanyl analogs constitute a particularly dangerous group of new psychoactive compounds responsible for many deaths around the world. Little is known about their metabolism, and studies utilizing liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) analysis of hepatocyte incubations and/or authentic urine samples do not allow for determination of the exact metabolite structures, especially when it comes to hydroxylated metabolites. In this study, seven motifs (2-, 3-, 4- and β-OH as well as 3,4-diOH, 4-OH-3-OMe and 3-OH-4-OMe) of fentanyl and five fentanyl analogs, acetylfentanyl, acrylfentanyl, cyclopropylfentanyl, isobutyrylfentanyl and 4F-isobutyrylfentanyl were synthesized. The reference standards were analyzed by LC-QTOF-MS, which enabled identification of the major metabolites formed in hepatocyte incubations of the studied fentanyls. By comparison with our previous data sets, major urinary metabolites could tentatively be identified. For all analogs, β-OH, 4-OH and 4-OH-3-OMe were identified after hepatocyte incubation. β-OH was the major hydroxylated metabolite for all studied fentanyls, except for acetylfentanyl where 4-OH was more abundant. However, the ratio 4-OH/β-OH was higher in urine samples than in hepatocyte incubations for all studied fentanyls. Also, 3-OH-4-OMe was not detected in any hepatocyte samples, indicating a clear preference for the 4-OH-3-OMe, which was also found to be more abundant in urine compared to hepatocytes. The patterns appear to be consistent across all studied fentanyls and could serve as a starting point in the development of methods and synthesis of reference standards of novel fentanyl analogs where nothing is known about the metabolism.

Liquid Chromatographic Multicomponent Method for Determination of Residues of Ipronidazole, Ronidazole, and Dimetridazole and Some Relevant Metabolites in Eggs, Plasma, and Feces and Its Use in Depletion Studies in Laying Hens

1991 ◽  
Vol 74 (1) ◽  
pp. 46-55 ◽  
Author(s):  
Rene M L Aerts ◽  
Irma M Egberink ◽  
Cornelis A Kan ◽  
Henk J Keukens ◽  
Wim M J Beek
Keyword(s):  
Laying Hens ◽  
Parent Compound ◽  
Animal Experiments ◽  
Sample Pretreatment ◽  
Side Chain ◽  
Hydroxylated Metabolites ◽  
Plasma Distribution ◽  
Liquid Chromatographic ◽  
Hydroxylated Metabolite

Abstract A simple, rapid liquid chromatographic (LC) method that uses UV/VIS detection has been developed for the determination In eggs of residues of the hlstomonostats dlmetridazole (DMZ), ronldazole (RON), Ipronidazole (IPR), and side-chain hydroxylated metabolites of DMZ and RON. Sample pretreatment Includes an aqueous extraction, purification with an Extrelut® cartridge, and acid partitioning with Isooctane. An aliquot of the final aqueous extract Is Injected Into a reversephase LC system; detection Is performed at 313 nm. The limits of determination are in the 5-10 µgkg range. A UV/ VIS spectrum can be obtained at the 10 µg/kg level by using diode-array UV/VIS detection. Recoveries are between 80 and 98% with a coefficient of variation of about 5%. Some 20 samples can be analyzed per day. A side-chain hydroxylated metabolite of IPR can also be detected with this method, as demonstrated with samples from animal experiments. After a single oral dose of the drugs to laying hens, residues of the parent compound and/or the hydroxylated metabolites could be detected In eggs 5-8 days after dosing. Plasma distribution and excretion in feces were established both with and without deconjugatlon. DMZ and IPR were extensively metabolized to hydroxylated nltrolmldazole metabolites; RON was excreted mainly as the parent compound.

Heuristic Solutions for a Class of Stochastic Uncapacitated p-Hub Median Problems

2019 ◽  
Vol 53 (4) ◽  
pp. 1126-1149 ◽  
Author(s):  
Juanjo Peiró ◽  
Ángel Corberán ◽  
Rafael Martí ◽  
Francisco Saldanha-da-Gama
Keyword(s):  
Data Sets ◽  
Heuristic Procedure ◽  
Median Problem ◽  
Stochastic Version ◽  
Deterministic Equivalent ◽  
Starting Point ◽  
Compact Formulation ◽  
Finite Set ◽  
Shipping Traffic

In this work, we propose a heuristic procedure for a stochastic version of the uncapacitated r-allocation p-hub median problem with nonstop services. In particular, we assume that the number of hubs to which a terminal can be allocated is bounded from above by r. Additionally, we consider the possibility of shipping traffic directly between terminals (nonstop services). Uncertainty is associated with the traffic to be shipped between nodes and with the transportation costs. If we assume that such uncertainty can be captured by a finite set of scenarios, each of which with a probability known in advance, it is possible to develop a compact formulation for the deterministic equivalent problem. However, even for small instances of the problem, the model becomes too large to be tackled by a general solver. This fact motivates the development of a heuristic procedure, whose starting point is the determination of a feasible solution to every (deterministic) single-scenario problem. These solutions are then embedded into a process based on the path relinking methodology: gradually an initial solution to the overall problem is transformed by the incorporation of attributes from some guiding solutions. In our case, the guiding solutions are those found for the single-scenario problems. We report and discuss the results of the numerical experiments performed using instances randomly generated for the new problem from the well-known CAB and AP data sets.

Determination of amphenicol antibiotics and their glucuronide metabolites in urine samples using liquid chromatography with quadrupole time-of-flight mass spectrometry

2020 ◽  
Vol 1146 ◽  
pp. 122122
Author(s):  
Marta Pastor-Belda ◽  
Natalia Campillo ◽  
Natalia Arroyo-Manzanares ◽  
Manuel Hernández-Córdoba ◽  
Pilar Viñas
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Time Of Flight ◽  
Urine Samples ◽  
Flight Mass Spectrometry

scholarly journals LC-QTOF-MS Identification of Major Urinary Cyclopropylfentanyl Metabolites Using Synthesized Standards

2019 ◽  
Vol 43 (8) ◽  
pp. 607-614 ◽  
Author(s):  
Svante Vikingsson ◽  
Tobias Rautio ◽  
Jakob Wallgren ◽  
Anna Åstrand ◽  
Shimpei Watanabe ◽  
...  
Keyword(s):  
United States ◽  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
The United States ◽  
Urine Samples ◽  
Post Mortem ◽  
Urinary Markers ◽  
Flight Mass Spectrometry ◽  
Fentanyl Analogs ◽  
Synthesis Routes

Abstract Cyclopropylfentanyl is a fentanyl analog implicated in 78 deaths in Europe and over 100 deaths in the United States, but toxicological information including metabolism data about this drug is scarce. The aim of this study was to provide the exact structure of abundant and unique metabolites of cyclopropylfentanyl along with synthesis routes. In this study, metabolites were identified in 13 post-mortem urine samples using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Samples were analyzed with and without enzymatic hydrolysis, and seven potential metabolites were synthesized in-house to provide the identity of major metabolites. Cyclopropylfentanyl was detected in all samples, and the most abundant metabolite was norcyclopropylfentanyl (M1) that was detected in 12 out of 13 samples. Reference materials were synthesized (synthesis routes provided) to identify the exact structure of the major metabolites 4-hydroxyphenethyl cyclopropylfentanyl (M8), 3,4-dihydroxyphenethyl cyclopropylfentanyl (M5) and 4-hydroxy-3-methoxyphenethyl cyclopropylfentanyl (M9). These metabolites are suitable urinary markers of cyclopropylfentanyl intake as they are unique and detected in a majority of hydrolyzed urine samples. Minor metabolites included two quinone metabolites (M6 and M7), not previously reported for fentanyl analogs. Interestingly, with the exception of norcyclopropylfentanyl (M1), the metabolites appeared to be between 40% and 90% conjugated in urine. In total, 11 metabolites of cyclopropylfentanyl were identified, including most metabolites previously reported after hepatocyte incubation.

Determination of urinary metabolites of XLR-11 by liquid chromatography–quadrupole time-of-flight mass spectrometry

2015 ◽  
Vol 408 (2) ◽  
pp. 503-516 ◽  
Author(s):  
Moonhee Jang ◽  
In Sook Kim ◽  
Yu Na Park ◽  
Jihyun Kim ◽  
Inhoi Han ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Time Of Flight ◽  
Urinary Metabolites ◽  
Flight Mass Spectrometry

Direct phase determination in electron crystallography: small organic molecules

1992 ◽  
Vol 50 (2) ◽  
pp. 1166-1167
Author(s):  
Douglas L. Dorset
Keyword(s):  
Organic Molecules ◽  
Data Sets ◽  
Temperature Structure ◽  
3D Analysis ◽  
Intensity Data ◽  
Electron Crystallography ◽  
Phase Determination ◽  
Measured Intensity ◽  
3D Data

The quantitative use of electron diffraction intensity data for the determination of crystal structures represents the pioneering achievement in the electron crystallography of organic molecules, an effort largely begun by B. K. Vainshtein and his co-workers. However, despite numerous representative structure analyses yielding results consistent with X-ray determination, this entire effort was viewed with considerable mistrust by many crystallographers. This was no doubt due to the rather high crystallographic R-factors reported for some structures and, more importantly, the failure to convince many skeptics that the measured intensity data were adequate for ab initio structure determinations.We have recently demonstrated the utility of these data sets for structure analyses by direct phase determination based on the probabilistic estimate of three- and four-phase structure invariant sums. Examples include the structure of diketopiperazine using Vainshtein's 3D data, a similar 3D analysis of the room temperature structure of thiourea, and a zonal determination of the urea structure, the latter also based on data collected by the Moscow group.

PHENOLIC METABOLITES OF DL-NORGESTREL: A METHOD FOR THE REMOVAL OF 1-HYDROXYLATED METABOLITES, POTENTIAL SOURCES OF PHENOLIC ARTIFACTS

1974 ◽  
Vol 76 (4) ◽  
pp. 789-800 ◽  
Author(s):  
Samuel F. Sisenwine ◽  
Ann L. Liu ◽  
Hazel B. Kimmel ◽  
Hans W. Ruelius
Keyword(s):  
Urinary Metabolites ◽  
Ion Exchange Resin ◽  
Gas Chromatography Mass Spectrometry ◽  
Phenolic Metabolites ◽  
Hydroxylated Metabolites ◽  
Analytical Work ◽  
Potential Sources ◽  
Alkaline Conditions ◽  
Artifact Formation ◽  
Work Up

ABSTRACT The identification of 1β-hydroxynorgestrel among the urinary metabolites of dl-norgestrel and the facile transformation of this compound under mild alkaline conditions to a potentially oestrogenic phenol provide an experimental basis for the conclusion advanced by others that the oestrogens present in the urine of subjects treated with synthetic progestens are artifacts formed during analytical work-up. A method has been devised which eliminates 1-hydroxylated metabolites as potential sources of phenolic artifacts. This method is based on the reduction by NaBH4 of the 1-hydroxy-4-en-3-one grouping in the A ring thereby excluding the possibility of aromatization during later fractionation on a basic ion exchange resin that separates neutral from phenolic metabolites. In the urines of women treated with 14C-dl-nogestrel, only 0.17–0.27% of the dose is found to have phenolic properties when this method is used. Two of the phenolic metabolites, 18-homoethynyloestradiol and 16β-hydroxy-18-homoethynyloestradiol, are present in amounts smaller than 0.01 % of the dose. Without the reduction steps the percentages are noticeably higher, indicating artifact formation under alkaline conditions. Similar results were obtained with urines from African Green Monkeys (Cercopithecus Aethiops) that had been dosed with 14C-dl-norgestrel. Radiolabelled 18-homoethynyloestradiol and 16β-hydroxy-18-homoethynyloestradiol were isolated from monkey urine and their identity confirmed by gas chromatography-mass spectrometry.

Sign in / Sign up

Export Citation Format

Share Document