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. 2022 Jan 24;27(3):763.
doi: 10.3390/molecules27030763.

Identification of the New Metabolite of Nebivolol Using Liquid Chromatography Coupled with High-Resolution Mass Spectrometry and Chemometrics

Jakub Trawiński  1 , Michał Wroński  1 , Maciej Gawlik  1 , Robert Skibiński  1
Affiliations

Identification of the New Metabolite of Nebivolol Using Liquid Chromatography Coupled with High-Resolution Mass Spectrometry and Chemometrics

Jakub Trawiński et al. Molecules. .

Abstract

In this study, the phase I hepatic metabolism pathway of a cardiovascular drug nebivolol was proposed on the basis of a human liver microsomes assay with the use of LC-HR-MS coupled with the chemometric method. Six biotransformation products were found with the assistance of chemometric analysis. Five of them were identified as the previously reported products of alicyclic hydroxylation and dihydroxylation, aromatic hydroxylation, as well as alicyclic oxidation of the parent compound. Moreover, one metabolite, not reported so far, was found to be a product of N-dealkylation of nebivolol-2-amino-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethan-1-ol. The novel metabolite was submitted to an in silico toxicity analysis to assess its biological properties. The applied computational methods indicated a significantly elevated risk of its mutagenic activity, compared to the parent molecule. Several metabolites of the nebivolol described in the literature were not detected in this study, indicating their non-hepatic origin.

Keywords: HLM; biotransformation; chromatography; drug metabolism; mass spectrometry; toxicity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Biotransformation of nebivolol in HLM.
Figure 2
Figure 2
Total ion current chromatograms (TIC) of nebivolol (NEB) after 60 min incubation with HLM ((A)—control; (B)—sample).
Figure 3
Figure 3
PCA biplot of HLM and Control samples (green) with the loadings (orange) of the entities (ions representing of the potential metabolites, expressed as nominal masses in Da).
Figure 4
Figure 4
MS/MS spectrum and fragmentation pattern of nebivolol.
Figure 5
Figure 5
MS/MS spectrum and fragmentation pattern of novel nebivolol metabolite (M6).
Figure 6
Figure 6
The proposed hepatic metabolic pathway of nebivolol.
See this image and copyright information in PMC

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