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1-(Benzo[b]thiophen-4-yl)piperazine Ring Induced Bioactivation of Brexpiprazole in Liver Microsomes: Identification and Characterization of Reactive Conjugates Using Ultra-High-Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

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Abstract

Background and Objectives

Brexpiprazole is an atypical antipsychotic approved for the treatment of schizophrenia and major depressive disorders in adults. The structure of brexpiprazole contains well-known structural alerts like a thiophene ring, piperazine ring and quinolinone motifs. Additionally, the literature reveals that its structural analog, aripiprazole, could generate reactive intermediates. However, the bioactivation potential of brexpiprazole is yet unknown. Therefore, this study was planned to identify and characterize reactive adducts of brexpiprazole and its metabolites.

Methods

Based on the reactivity, the potential atomic sites for a reactive intermediate generation were predicted by a xenosite web predictor tool for glutathione, cyanide, protein and DNA. To study the metabolic activation of brexpiprazole, the drug was individually incubated for 2 h at 37 °C with pooled male rat liver microsomes and human liver microsomes in microcentrifuge tubes fortified with glutathione/N-acetyl cysteine. Nicotinamide adenine dinucleotide phosphate reduced tetrasodium salt was used as a co-factor.

Results

A total of six glutathione and N-acetyl cysteine conjugates of brexpiprazole metabolites were identified and characterized using ultra‐high‐performance liquid chromatography/quadrupole time‐of‐flight tandem mass spectrometry. Reactive metabolite 1 (RM1), RM3, RM4 and RM6 reactive conjugates were formed due to reactive quinone-imine or quinone intermediates, while RM2 and RM5 reactive adducts were generated because of a thiophene-S-oxide intermediate.

Conclusion

Brexpirazole is bioactivated due to the presence of a 1-(benzo[b]thiophen-4-yl)piperazine ring in its structure. In contrast to aripiprazole, the quinolinone motif was found latent towards bioactivation in brexpiprazole.

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Acknowledgements

The authors are grateful to CTX Lifesciences Pvt. Ltd. (Surat, India) for providing the gift sample of brexpiprazole. The authors are grateful to the Director of NIPER-Ahmedabad, Prof. Kiran Kalia, for providing research facilities. The authors also want to acknowledge the Department of Pharmaceuticals, Ministry of Chemical and Fertilizer, New Delhi, India, for providing a research fellowship.

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Authors and Affiliations

  1. National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), Palaj, Gandhinagar, Gujarat, 382355, India

    Disha Thakkar & Abhijeet S. Kate

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  1. Disha Thakkar
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  2. Abhijeet S. Kate
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Correspondence to Abhijeet S. Kate.

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Funding

The study was funded by research fellowship provided by the Department of Pharmaceuticals, Ministry of Chemical and Fertilizer, New Delhi, India.

Conflict of interest

Disha Thakkar and Abhijeet S. Kate have no conflict of interest.

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Thakkar, D., Kate, A.S. 1-(Benzo[b]thiophen-4-yl)piperazine Ring Induced Bioactivation of Brexpiprazole in Liver Microsomes: Identification and Characterization of Reactive Conjugates Using Ultra-High-Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry. Eur J Drug Metab Pharmacokinet 45, 393–403 (2020). https://doi.org/10.1007/s13318-020-00606-8

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  • DOI: https://doi.org/10.1007/s13318-020-00606-8

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