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. 2021 Jun 22;26(13):3794.
doi: 10.3390/molecules26133794.

Characterization of Phase I Hepatic Metabolites of Anti-Premature Ejaculation Drug Dapoxetine by UHPLC-ESI-Q-TOF

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

Characterization of Phase I Hepatic Metabolites of Anti-Premature Ejaculation Drug Dapoxetine by UHPLC-ESI-Q-TOF

Robert Skibiński et al. Molecules. .

Abstract

Determination of the metabolism pathway of xenobiotics undergoing the hepatic pass is a crucial aspect in drug development since the presence of toxic biotransformation products may result in significant side effects during the therapy. In this study, the complete hepatic metabolism pathway of dapoxetine established according to the human liver microsome assay with the use of a high-resolution LC-MS system was described. Eleven biotransformation products of dapoxetine, including eight metabolites not reported in the literature so far, were detected and identified. N-dealkylation, hydroxylation, N-oxidation and dearylation were found to be the main metabolic reactions for the investigated xenobiotic. In silico analysis of toxicity revealed that the reaction of didesmethylation may contribute to the increased carcinogenic potential of dapoxetine metabolites. On the other hand, N-oxidation and aromatic hydroxylation biotransformation reactions possibly lead to the formation of mutagenic compounds.

Keywords: HLM; biotransformation; chromatography; in silico toxicity; mass spectrometry; metabolites.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overlapped extracted ion chromatograms (EIC) of dapoxetine (DAP) and its metabolites (M1–M11) after a 30-min incubation with HLM.
Figure 2
Figure 2
Biotransformation of dapoxetine in HLM (presented as the function of time; error bars represent the standard deviation of the mean, n = 3).
Figure 3
Figure 3
Evolution profiles of the dapoxetine metabolites (A,B) formed in HLM (presented as the function of time; error bars represent the standard deviation of the mean, n = 3).
Figure 4
Figure 4
The proposed hepatic metabolic pathway of dapoxetine (location of the hydroxyl group involves the whole naphthalene ring).
See this image and copyright information in PMC

References

    1. Almazroo O.A., Miah M.K., Venkataramanan R. Drug Metabolism in the Liver. Clin. Liv. Dis. 2017;21:1–20. doi: 10.1016/j.cld.2016.08.001. - DOI - PubMed
    1. Remmer H. The role of the liver in drug metabolism. Am. J. Med. 1970;49:617–629. doi: 10.1016/S0002-9343(70)80129-2. - DOI - PubMed
    1. Danielson P.B. The Cytochrome P450 Superfamily: Biochemistry, Evolution and Drug Metabolism in Humans. [(accessed on 19 January 2020)]; Available online: http://www.eurekaselect.com/64118/article. - PubMed
    1. McDonnell A.M., Dang C.H. Basic Review of the Cytochrome P450 System. J. Adv. Pract. Oncol. 2013;4:263–268. - PMC - PubMed
    1. Meunier B., de Visser S.P., Shaik S. Mechanism of Oxidation Reactions Catalyzed by Cytochrome P450 Enzymes. Chem. Rev. 2004;104:3947–3980. doi: 10.1021/cr020443g. - DOI - PubMed

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