Major Metabolites of Zolpidem: Expeditious Synthesis and Mass Spectra

Klupsch, Frédérique; Houssin, Raymond; Humbert, Luc; Imbenotte, M.; Hénichart, Jean‐Pierre; Lhermitte, Michel

doi:10.1248/cpb.54.1318

Cited by 13 publications

(6 citation statements)

References 13 publications

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“…For mono‐oxygenated‐zolpidem isomers M1 and M2, the loss of CH 2 O from the pseudo‐molecular ions to produce a fragment at m / z 294.1603 indicated that each of these metabolites contained a hydroxyl group on one of the two primary carbon substituents of the aromatic rings. Furthermore, the MS/MS spectrum of carboxyzolpidem (M5) contained product ions at m / z 221.1074, 265.0974, and 293.0923, which is consistent with the previously reported11 MS/MS spectrum of N , N ,6‐Trimethyl‐2‐(4‐carboxyphenyl)‐imidazo[1,2‐ a ]pyridine‐3‐acetamide (zolpidem with a methyl group on the phenyl ring replaced by a carboxy function). These authors also previously reported the MS/MS spectrum of N , N ,dimethyl‐6‐carboxy‐2‐(4‐methylphenyl)‐imidazo[1,2‐ a ]pyridine‐3‐acetamide (zolpidem with a methyl group on the imidazo[1,2‐ a ]pyridine ring replaced by a carboxy function).…”

Section: Resultssupporting

confidence: 91%

“…These authors also previously reported the MS/MS spectrum of N , N ,dimethyl‐6‐carboxy‐2‐(4‐methylphenyl)‐imidazo[1,2‐ a ]pyridine‐3‐acetamide (zolpidem with a methyl group on the imidazo[1,2‐ a ]pyridine ring replaced by a carboxy function). In contrast to the former carboxyzolpidem isomer, this second previously reported isomer lacked a product ion at m / z 221 and instead produced a fragment at m / z 219 11. Taken together from the results of the current study, the presence of m / z 221.1075 in the spectrum of mono‐oxygenated‐zolpidem isomer M1 and its absence from that of M2, indicate that the positions of hydroxylation in these two isomers are on the primary methyl groups attached to the phenyl and imidazo[1,2‐ a ]pyridine rings respectively.…”

Section: Resultsmentioning

confidence: 59%

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In vitro metabolism of tiletamine, zolazepam and nonbenzodiazepine sedatives: Identification of target metabolites for equine doping control

Fenwick¹,

Scarth²

2011

Drug Testing and Analysis

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Within horseracing, the detection of prohibited substance doping often requires urine analysis; hence, it is necessary to understand the metabolism of the drugs in question. Here, the previously unknown equine metabolism of eight sedatives is reported in order to provide information on target metabolites for use in doping control. Phase I metabolite information was provided by incubation with equine liver S9 fraction. In vitro techniques were chosen in order to reduce the ethical and financial issues surrounding the study of so many compounds, none of which are licensed for use in horses in the UK. Several metabolites of each drug were identified using liquid chromatography-high resolution mass spectrometric (LC-HRMS) analysis on an LTQ-Orbitrap. Further structural information was obtained by tandem mass spectrometry (MS/MS) analysis; allowing postulation of the structure of some of the most abundant in vitro metabolites. The most abundant metabolites of alpidem, etifoxine, indiplon, tiletamine, zaleplon, zolazepam, zolpidem, and zopiclone related to hydroxylation/N-oxidation, deethylation, demethylation, deethylation, hydroxylation/N-oxidation, demethylation, hydroxylation/N-oxidation and hydroxylation/N-oxidation, respectively. In many cases, further work would be required to fully elucidate the precise positioning of the functional groups involved. The results of this study provide metabolite information that can be used to enhance equine anti-doping screening methods. However, the in vitro metabolites identified are at present only a prediction of those that may occur in vivo. In the future, any positive findings of these drugs and/or their metabolites in horse urine samples could help validate these findings and/or refine the choice of target metabolites.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 59%

In vitro metabolism of tiletamine, zolazepam and nonbenzodiazepine sedatives: Identification of target metabolites for equine doping control

Fenwick¹,

Scarth²

2011

Drug Testing and Analysis

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“…6f) elutes after the parent drug which would be in line with its postulated N-oxide structure. Finally, the mass shifts of +30 mass units in both side chain fragments in comparison to the parent can be assigned to the tolyl carboxy metabolite which has also been described in the literature [30,31].…”

Section: Identification Of Metabolitesmentioning

confidence: 73%

“…6e). Both of these metabolic reactions have been described in the literature [30,31]. A further hydroxy metabolite carrying the hydroxyl function at the tolyl moiety has also been described in the literature [30].…”

Section: Identification Of Metabolitesmentioning

confidence: 92%

Studies on the metabolism of five model drugs by fungi colonizing cadavers using LC-ESI-MS/MS and GC-MS analysis

2012

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It is well-known that cadavers may be colonized by microorganisms, but there is limited information if or to what extent these microbes are capable of metabolizing drugs or poisons, changing the concentrations and metabolic pattern of such compounds in postmortem samples. The aim of the present study was to develop a fungal biotransformation system as an in vitro model to investigate potential postmortem metabolism by fungi. Five model drugs (amitriptyline, metoprolol, mirtazapine, promethazine, and zolpidem) were each incubated with five model fungi known to colonize cadavers (Absidia repens, Aspergillus repens, Aspergillus terreus, Gliocladium viride, and Mortierella polycephala) and with Cunninghamella elegans (positive control). Incubations were performed in Sabouraud medium at 25 °C for 5 days. After centrifugation, a part of the supernatants was analyzed by liquid chromatography-tandem mass spectrometry with product ion scanning. Another part was analyzed by full scan gas chromatography-mass spectrometry after extraction and derivatization. All model drugs were metabolized by the control fungus resulting in two (metoprolol) to ten (amitriptyline) metabolites. Of the model fungi, only Abs. repens and M. polycephala metabolized the model drugs: amitriptyline was metabolized to six and five, metoprolol to two and two, mirtazapine to five and three, promethazine to six and nine, and zolpidem to three and four metabolites, respectively. The main metabolic reactions were demethylation, oxidation, and hydroxylation. The presented in vitro model is applicable to studying drug metabolism by fungi colonizing cadavers.

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“…Pour établir les fenêtres de détection du zolpidem et de ses métabolites dans les urines, les métabolites I et II ont été synthétisés [11], puis une méthode d'extraction en phase solide (SPE) et de détection par UPLC-MS/MS a été développée.…”

Section: Introductionunclassified

Élargissement de la fenêtre de détection du zolpidem par la recherche de ses métabolites urinaires dans le cadre de la soumission chimique

et al. 2008

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Résumé -Objectif : Dans le cadre de la soumission chimique, une méthode UPLC-MS/MS a été développée pour dé-tecter le zolpidem et ses métabolites dans les urines. Méthodes : Pour déterminer les fenêtres de détection du zolpidem et de ses métabolites dans les urines, un volontaire a pris un comprimé de 10 mg. Les urines ont ensuite été collectées 30 min et 1 h après l'administration puis toutes les 12 h pendant 144 h. Après extraction sur cartouches Oasis MCX (SPE), les urines ont été analysées sur une colonne ACQUITY UPLC T M BEH C18, 1,7 µm (2, 1 × 100 mm) avec un gradient d'acide formique 0,1 % et d'acétonitrile, la détection a été effectuée au moyen d'un spectromètre de masse en tandem en utilisant deux transitions par composé. Résultats : Le zolpidem est détecté pendant 60 h, avec un pic après 12 h. Le métabolite I (acide 4-[(3-diméthylcarboylméthyl-6-méthyl)-imidazo-[1,2a]pyridine-2-yl]-benzoïque) est détecté jusqu'au dernier temps de la cinétique, tandis que le métabolite II (acide 3-diméthylcarbamoylméthyl-2-(4-méthylphényl)-imidazo-[1,2a]-pyridine-6-carboxylique) est détecté jusque 84 h après l'administration. Conclusion : Ainsi, dans le cas de soumission chimique impliquant le zolpidem, dans les urines le métabolite I apparaît être le meilleur marqueur pour caractériser une exposition. Mots clés : Zolpidem, urine, soumission chimique, UPLC-MS/MSAbstract -Objectif : An UPLC-MS/MS method was developed to detect zolpidem and its metabolites in urine in case of drug facilitated crimes. Methods : To establish the windows of detection zolpidem and its metabolites in urine, a volunteer received a 10 mg dose. Urine specimens were collected 30 min and 1 h after administration then each 12 h for 144 h. After extraction on cartridge Oasis MCX (SPE), the extracts were injected into an ACQUITY UPLCTM BEH C18, 1,7 µm (2, 1 × 100 mm) column using a gradient formic acid 0.1% and acetonitrile. Detection was achieved by tandem mass spectrometry operating in multiple reaction monitoring (MRM) mode. Two transitions were monitored for each compound. Results : Zolpidem was detected until 60 h with peak concentration after 12 h. Metabolite I (4-[(3-dimethylcarboylmethyl-6-methyl)-imidazo-[1,2a]pyridin-2-yl]-benzoic acid was detected until 144 h, whereas metabolite II (3-dimethylcarbamoylmethyl-2-(4-methylphenyl) imidazo-[1,2a]-pyridine-6-carboxylic acid) was detected until 84 h after administration. Conclusion : Therefore, in case of drug facilitated crimes involving zolpidem, the metabolite I appears as the best marker to document an exposition.

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Major Metabolites of Zolpidem: Expeditious Synthesis and Mass Spectra

Cited by 13 publications

References 13 publications

In vitro metabolism of tiletamine, zolazepam and nonbenzodiazepine sedatives: Identification of target metabolites for equine doping control

In vitro metabolism of tiletamine, zolazepam and nonbenzodiazepine sedatives: Identification of target metabolites for equine doping control

Studies on the metabolism of five model drugs by fungi colonizing cadavers using LC-ESI-MS/MS and GC-MS analysis

Élargissement de la fenêtre de détection du zolpidem par la recherche de ses métabolites urinaires dans le cadre de la soumission chimique

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