Formation of cytotoxic protein reactive metabolites from furosemide: Biological consequences of drug metabolism

Background: Analytical scientists have constantly been in search for more efficient and economical methods for drug simulation studies. Owing to great progress in this field, there are various techniques available nowadays that mimic drug metabolism in the hepatic microenvironment. The conventional in vitro and in vivo studies pose inherent methodological drawbacks due to which alternative analytical approaches are devised for different drug metabolism experiments. Methods: Electrochemistry has gained attention due to its benefits over conventional metabolism studies. Because of the protein binding nature of reactive metabolites, it is difficult to identify them directly after formation, although the use of trapping agents aids in their successful identification. Furthermore, various scientific reports confirmed the successful simulation of drug metabolism studies by electrochemical cells. Electrochemical cells coupled with chromatography and mass spectrometry made it easy for direct detection of reactive metabolites. In this review, an insight into the application of electrochemical techniques for metabolism simulation studies has been provided. The sole use of electrochemical cells, as well as their setups on coupling to liquid chromatography and mass spectrometry has been discussed. The importance of metabolism prediction in early drug discovery and development stages along with a brief overview of other conventional methods has also been highlighted. Conclusion: To the best of our knowledge, this is the first article to review the electrochemistry based strategy for the analysis of reactive metabolites. The outcome of this ‘first of its kind’ review will significantly help the researchers in the application of electrochemistry based bioanalysis for metabolite detection.

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Meeting of the Drug Metabolism Group Reactive metabolites—do they always mean toxicity?

Xenobiotica ◽

10.3109/00498257909034705 ◽

1979 ◽

Vol 9 (1) ◽

pp. 63-64 ◽

Cited By ~ 2

Author(s):

J. Caldwell

Keyword(s):

Drug Metabolism ◽

Reactive Metabolites

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Drug Metabolism and Reactive Metabolites

Hit and Lead Profiling - Methods and Principles in Medicinal Chemistry ◽

10.1002/9783527627448.ch7 ◽

2009 ◽

pp. 145-163

Author(s):

Alan P. Watt

Keyword(s):

Drug Metabolism ◽

Reactive Metabolites

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Monooxygenase- and Dioxygenase-Catalyzed Oxidative Dearomatization of Thiophenes by Sulfoxidation, cis-Dihydroxylation and Epoxidation

International Journal of Molecular Sciences ◽

10.3390/ijms23020909 ◽

2022 ◽

Vol 23 (2) ◽

pp. 909

Author(s):

Derek R. Boyd ◽

Narain D. Sharma ◽

Paul J. Stevenson ◽

Patrick Hoering ◽

Christopher C. R. Allen ◽

...

Keyword(s):

Molecular Docking ◽

Pharmaceutical Industry ◽

Drug Metabolism ◽

Absolute Configuration ◽

Chemoenzymatic Synthesis ◽

Enzymatic Oxidation ◽

Reactive Metabolites ◽

Substrate Type ◽

Oxidative Dearomatization ◽

Factors Associated

Enzymatic oxidations of thiophenes, including thiophene-containing drugs, are important for biodesulfurization of crude oil and drug metabolism of mono- and poly-cyclic thiophenes. Thiophene oxidative dearomatization pathways involve reactive metabolites, whose detection is important in the pharmaceutical industry, and are catalyzed by monooxygenase (sulfoxidation, epoxidation) and dioxygenase (sulfoxidation, dihydroxylation) enzymes. Sulfoxide and epoxide metabolites of thiophene substrates are often unstable, and, while cis-dihydrodiol metabolites are more stable, significant challenges are presented by both types of metabolite. Prediction of the structure, relative and absolute configuration, and enantiopurity of chiral metabolites obtained from thiophene enzymatic oxidation depends on the substrate, type of oxygenase selected, and molecular docking results. The racemization and dimerization of sulfoxides, cis/trans epimerization of dihydrodiol metabolites, and aromatization of epoxides are all factors associated with the mono- and di-oxygenase-catalyzed metabolism of thiophenes and thiophene-containing drugs and their applications in chemoenzymatic synthesis and medicine.

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