New finding of nalbuphine metabolites in men: NMR spectroscopy and UPLC-MS/MS spectrometry assays in a pilot human study

Hong Jaan Wang, Cheng Huei Hsiong, Li Heng Pao, Wen Liang Chang, Li Jie Zhang, Min Jen Lin, Shung Tai Ho, Pei Wei Huang, Oliver Yoa Pu Hu

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

A safe and efficient semi-synthetic narcotic nalbuphine (NAL) which was broadly applied in analgesic therapy has long been considered to eliminate from human body via phase II conjugation. However, up to the present, neither the complete metabolic pathways nor the identified metabolites of NAL have been clarified in documented reports. In this study, four novel metabolites were discovered by incubating NAL with human liver microsomes. These metabolites were later quantified in blood samples from human volunteers treated with NAL. An accurate and precise new method for simultaneously determining NAL and its metabolites was also established. Their chemical structures were elucidated on the basis of one- and two-dimensional NMR spectroscopic analyses including 1H-1H correlation spectroscopy, nuclear overhauser enhancement spectroscopy, heteronuclear single-quantum correlation, and heteronuclear multiple bond correlation, and further confirmed by mass spectrometry. The analytical method was validated and applied successfully to a pilot human study with ultra-high performance liquid chromatography-tandem mass spectrometry employed with positive ion electrospray ionization via multiple reaction monitoring mode. This is the first report on the qualitative and quantitative analysis of NAL coupled with its two hydroxylated (3′-hydroxynalbuphine and 4′-hydroxynalbuphine) and two conjugated metabolites (nalbuphine-3-β-d-glucuronide and nalbuphine-6-β-d-glucuronide). The present method offers a rapid and simple way of performing pharmacokinetic studies of NAL, and assists in elucidating its metabolic pathway in humans.

Original languageEnglish
Pages (from-to)709-718
Number of pages10
JournalMetabolomics
Volume10
Issue number4
DOIs
Publication statusPublished - Jan 1 2014
Externally publishedYes

Keywords

  • Metabolite
  • Nalbuphine
  • NMR
  • P450
  • UGT
  • UPLC-MS/MS

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism

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    Wang, H. J., Hsiong, C. H., Pao, L. H., Chang, W. L., Zhang, L. J., Lin, M. J., Ho, S. T., Huang, P. W., & Hu, O. Y. P. (2014). New finding of nalbuphine metabolites in men: NMR spectroscopy and UPLC-MS/MS spectrometry assays in a pilot human study. Metabolomics, 10(4), 709-718. https://doi.org/10.1007/s11306-013-0605-y