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Chiral analyses of dextromethorphan/levomethorphan and their metabolites in rat and human samples using LC-MS/MS

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Abstract

In order to develop an analytical method for the discrimination of dextromethorphan (an antitussive medicine) from its enantiomer, levomethorphan (a narcotic) in biological samples, chiral analyses of these drugs and their O-demethyl and/or N-demethyl metabolites in rat plasma, urine, and hair were carried out using LC-MS/MS. After the i.p. administration of dextromethorphan or levomethorphan to pigmented hairy male DA rats (5 mg/kg/day, 10 days), the parent compounds and their three metabolites in plasma, urine and hair were determined using LC-MS/MS. Complete chiral separation was achieved in 12 min on a Chiral CD-Ph column in 0.1% formic acid–acetonitrile by a linear gradient program. Most of the metabolites were detected as being the corresponding O-demethyl and N, O-didemethyl metabolites in the rat plasma and urine after the hydrolysis of O-glucuronides, although obvious differences in the amounts of these metabolites were found between the dextro and levo forms. No racemation was observed through O- and/or N-demethylation. In the rat hair samples collected 4 weeks after the first administration, those differences were more clearly detected and the concentrations of the parent compounds, their O-demethyl, N-demethyl, and N, O-didemethyl metabolites were 63.4, 2.7, 25.1, and 0.7 ng/mg for the dextro forms and 24.5, 24.6, 2.6, and 0.5 ng/mg for the levo forms, respectively. In order to fully investigate the differences of their metabolic properties between dextromethorphan and levomethorphan, DA rat and human liver microsomes were studied. The results suggested that there might be an enantioselective metabolism of levomethorphan, especially with regard to the O-demethylation, not only in DA rat but human liver microsomes as well. The proposed chiral analyses might be applied to human samples and could be useful for discriminating dextromethorphan use from levomethorphan use in the field of forensic toxicology, although further studies should be carried out using authentic human samples.

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Acknowledgments

Part of this work was supported by a Health and Labor Sciences Research Grant from the Ministry of Health, Labor and Welfare in Japan.

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Authors and Affiliations

  1. Division of Pharmacognosy, Phytochemistry and Narcotics, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo, 158-8501, Japan

    Ruri Kikura-Hanajiri, Maiko Kawamura & Yukihiro Goda

  2. Division of Medical Devices, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo, 158-8501, Japan

    Atsuko Miyajima

  3. Division of Pharmacology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo, 158-8501, Japan

    Momoko Sunouchi

Authors
  1. Ruri Kikura-Hanajiri
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  2. Maiko Kawamura
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  3. Atsuko Miyajima
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  4. Momoko Sunouchi
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  5. Yukihiro Goda
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Correspondence to Ruri Kikura-Hanajiri.

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Published in the special issue Forensic Toxicology with Guest Editors Frank T. Peters, Hans H. Maurer, and Frank Musshoff.

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Kikura-Hanajiri, R., Kawamura, M., Miyajima, A. et al. Chiral analyses of dextromethorphan/levomethorphan and their metabolites in rat and human samples using LC-MS/MS. Anal Bioanal Chem 400, 165–174 (2011). https://doi.org/10.1007/s00216-011-4707-y

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  • DOI: https://doi.org/10.1007/s00216-011-4707-y

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