Skip to main content
main-content
Erschienen in: Forensic Toxicology 1/2021

17.09.2020 | Original Article

Qualitative analysis of zolpidem and its metabolites M-1 to M-4 in human blood and urine using liquid chromatography–tandem mass spectrometry

verfasst von: Koji Yamaguchi, Hajime Miyaguchi, Keiko Hirakawa, Youkichi Ohno, Yoshimasa Kanawaku

Erschienen in: Forensic Toxicology | Ausgabe 1/2021

Einloggen, um Zugang zu erhalten

Abstract

Purpose

The aim of this study was to develop the method for the qualitative analysis of zolpidem and its metabolites M-1 to M-4 using liquid chromatography–tandem mass spectrometry (LC–MS/MS) in human blood and urine.

Methods

To obtain analytical standards, a method for synthesizing zolpidem metabolites M-1 to M-4 was developed. A combination of a copper-catalyzed three-component coupling reaction and pyrrolidine-catalyzed imine formation was adopted to synthesize the methyl esters of M-1 (M-1-Me) and M-2 (M-2-Me), which were hydrolyzed to afford M-1 and M-2, respectively. M-3 and M-4 were also synthesized. The LC–MS/MS conditions were optimized using authentic standards. M-1 to M-4 were analyzed in human blood and urine.

Results

M-1 to M-4 were successfully synthesized. The mass spectra of M-1 and M-2 were almost identical, but their peaks were chromatographically separated using a octadecyl silica column. Likewise, mass spectra of M-3 and M-4 were similar, but their peaks were chromatographically separated. The peak intensities of the metabolites in human blood and urine were M-1 > M-2, and M-4 > M-3; M-3 was detected only in urine. The presence of other hydroxyzolpidems was also revealed.

Conclusions

Chromatographic separation of M-1 and M-2 and that of M-4 and other hydroxyzolpidems is necessary to analyze zolpidem metabolites in biological matrices because their mass spectra are quite similar. This study is the first to analyze zolpidem and M-1 to M-4 simultaneously using LC–MS/MS, which can provide more compelling evidence of zolpidem intake.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Zhou J, Yamaguchi K, Ohno Y (2014) Quantitative analysis of quazepam and its metabolites in human blood, urine, and bile by liquid chromatography-tandem mass spectrometry. Forensic Sci Int 241:e5–12 CrossRef Zhou J, Yamaguchi K, Ohno Y (2014) Quantitative analysis of quazepam and its metabolites in human blood, urine, and bile by liquid chromatography-tandem mass spectrometry. Forensic Sci Int 241:e5–12 CrossRef
2.
Zurück zum Zitat Hajak G, Müller WE, Wittchen HU, Pittrow D, Kirch W (2003) Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction 98:1371–1378 CrossRef Hajak G, Müller WE, Wittchen HU, Pittrow D, Kirch W (2003) Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction 98:1371–1378 CrossRef
3.
Zurück zum Zitat Ascalone V, Flaminio L, Guinebault P, Thenot JP, Morselli PL (1992) Determination of zolpidem, a new sleep-inducing agent, and its metabolites in biological fluids: pharmacokinetics, drug metabolism and investigations in humans. J Chromatogr 581:237–250 CrossRef Ascalone V, Flaminio L, Guinebault P, Thenot JP, Morselli PL (1992) Determination of zolpidem, a new sleep-inducing agent, and its metabolites in biological fluids: pharmacokinetics, drug metabolism and investigations in humans. J Chromatogr 581:237–250 CrossRef
4.
Zurück zum Zitat Mingozzi M, Manzoni L, Arosio D, Dal Corso A, Manzotti M, Innamorati F, Pignataro L, Lecis D, Delia D, Seneci P, Gennari C (2014) Synthesis and biological evaluation of dual action cyclo-RGD/SMAC mimetic conjugates targeting α(v)β(3)/α(v)β(5) integrins and IAP proteins. Org Biomol Chem 12:3288–3302 CrossRef Mingozzi M, Manzoni L, Arosio D, Dal Corso A, Manzotti M, Innamorati F, Pignataro L, Lecis D, Delia D, Seneci P, Gennari C (2014) Synthesis and biological evaluation of dual action cyclo-RGD/SMAC mimetic conjugates targeting α(v)β(3)/α(v)β(5) integrins and IAP proteins. Org Biomol Chem 12:3288–3302 CrossRef
5.
Zurück zum Zitat Chernyak N, Gevorgyan V (2010) General and efficient copper-catalyzed three-component coupling reaction towards imidazoheterocycles: one-pot synthesis of alpidem and zolpidem. Angew Chem Int Ed Engl 49:2743–2746 CrossRef Chernyak N, Gevorgyan V (2010) General and efficient copper-catalyzed three-component coupling reaction towards imidazoheterocycles: one-pot synthesis of alpidem and zolpidem. Angew Chem Int Ed Engl 49:2743–2746 CrossRef
6.
Zurück zum Zitat Morales S, Guijarro FG, García Ruano JL, Cid MB (2014) A general aminocatalytic method for the synthesis of aldimines. J Am Chem Soc 136:1082–1089 CrossRef Morales S, Guijarro FG, García Ruano JL, Cid MB (2014) A general aminocatalytic method for the synthesis of aldimines. J Am Chem Soc 136:1082–1089 CrossRef
7.
Zurück zum Zitat Allen J, Georges P (1985) Derives d'imidazopyridine, leur preparation et leur application en therapeutique. France Patent FR2581646 Allen J, Georges P (1985) Derives d'imidazopyridine, leur preparation et leur application en therapeutique. France Patent FR2581646
8.
Zurück zum Zitat Klupsch F, Houssin R, Humbert L, Imbenotte M, Henichart JP, Lhermitte M (2006) Major metabolites of zolpidem: expeditious synthesis and mass spectra. Chem Pharm Bull 54:1318–1321 CrossRef Klupsch F, Houssin R, Humbert L, Imbenotte M, Henichart JP, Lhermitte M (2006) Major metabolites of zolpidem: expeditious synthesis and mass spectra. Chem Pharm Bull 54:1318–1321 CrossRef
9.
Zurück zum Zitat Thénot JP, Hermann P, Durand A, Burke JT, Allen J, Garrigou D, Vajta S, Albin H, Thébault JJ, Olive G, Warrington SJ (1988) Pharmacokinetics and metabolism of zolpidem in various species and in human. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders. Raven Press, New York, pp 139–153 Thénot JP, Hermann P, Durand A, Burke JT, Allen J, Garrigou D, Vajta S, Albin H, Thébault JJ, Olive G, Warrington SJ (1988) Pharmacokinetics and metabolism of zolpidem in various species and in human. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders. Raven Press, New York, pp 139–153
10.
Zurück zum Zitat Yamaguchi K, Fugami M, Ishikawa S, Ohno Y (2016) Analysis of zolpidem metabolites in human bile: identification of hydroxyzolpidems by LC-MS/MS and chemical synthesis. In: The 54th annual meeting of the international association of forensic toxicologists, Brisbane, Australia Yamaguchi K, Fugami M, Ishikawa S, Ohno Y (2016) Analysis of zolpidem metabolites in human bile: identification of hydroxyzolpidems by LC-MS/MS and chemical synthesis. In: The 54th annual meeting of the international association of forensic toxicologists, Brisbane, Australia
11.
Zurück zum Zitat Hampel G, Blaschke G (1996) Direct determination of zolpiem and its main metabolites in urine using capillary electrophoresis with laser-induced fluorescence detection. J Chromatogr B 675:131–137 CrossRef Hampel G, Blaschke G (1996) Direct determination of zolpiem and its main metabolites in urine using capillary electrophoresis with laser-induced fluorescence detection. J Chromatogr B 675:131–137 CrossRef
Metadaten
Titel
Qualitative analysis of zolpidem and its metabolites M-1 to M-4 in human blood and urine using liquid chromatography–tandem mass spectrometry
verfasst von
Koji Yamaguchi
Hajime Miyaguchi
Keiko Hirakawa
Youkichi Ohno
Yoshimasa Kanawaku
Publikationsdatum
17.09.2020
Verlag
Springer Singapore
Erschienen in
Forensic Toxicology / Ausgabe 1/2021
Print ISSN: 1860-8965
Elektronische ISSN: 1860-8973
DOI
https://doi.org/10.1007/s11419-020-00551-w

Weitere Artikel der Ausgabe 1/2021

Forensic Toxicology 1/2021 Zur Ausgabe

Neu im Fachgebiet Rechtsmedizin

Open Access 15.08.2022 | Mammakarzinom | CME

Prädiktive molekulare Diagnostik beim Mammakarzinom

Welche Anforderungen stellen sich heute und in Zukunft für die Pathologie?

10.08.2022 | Schwerpunkt: Akkreditierung und Zertifizierung (Qualitätssicherung)

Ringversuche – ein zentrales Mittel der externen Qualitätssicherung

03.08.2022 | Schwerpunkt: Akkreditierung und Zertifizierung (Qualitätssicherung)

Akkreditierung in der Pathologie und Neuropathologie

Wege und Pitfalls

25.07.2022 | Schwerpunkt: Akkreditierung und Zertifizierung (Qualitätssicherung)

Die Akkreditierung in der Pathologie und Neuropathologie in Deutschland

Rahmenbedingungen und Voraussetzungen