Simulation of phase I metabolism reactions of selected calcium channel blockers by human liver microsomes and photochemical methods with the use of Q-TOF LC/MS

• Published in: Journal of pharmaceutical and biomedical analysis 2019-10, Vol.175, p.112776-112776, Article 112776
• Main Authors: Gawlik, Maciej, Trawiński, Jakub, Skibiński, Robert
• Format: Article
• Language: English
• Subjects: Calcium Channel Blockers - metabolism; Chromatography, High Pressure Liquid - methods; Drug metabolism; Flunarizine; Humans; Mass spectrometry; Metabolic Clearance Rate - physiology; Microsomes, Liver - metabolism; Perhexiline; Photocatalysis; Photochemistry - methods; Spectrometry, Mass, Electrospray Ionization - methods; Tandem Mass Spectrometry - methods
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2019.07.024

[Display omitted] •Previously unreported metabolites of perhexiline and flunarizine were detected and their chemical structures were elucidated.•Chemometric method was used for multivariate comparison of photochemical and HLM biological metabolic profiles.•Photochemical method was found to be a complementary method for predicting phase I metabolism reactions.•in silico toxicity and mutagenicity assessment of the characterized metabolites were evaluated. The in vitro phase I metabolism of perhexiline and flunarizine, two calcium channel blockers was investigated during this study with the use of human liver microsomes (HLM) method compared with TiO2, WO3 and ZnO catalyzed photochemical reaction. In order to determine the structures of metabolites an quadrupole time-of-flight mass spectrometry combined with liquid chromatography (Q-TOF LC/MS) system was used. The obtained high resolution mass spectra enabled to identify thirteen products of metabolism of selected drugs including three not yet described metabolites of perhexiline and two new metabolites of flunarizine. The vast majority of metabolites were confirmed also with the participation of photocatalytic approach of the drug metabolism simulation. The comparison of all metabolic profiles made with the use of computational methods drew attention particularly to TiO2 and WO3 catalyzed photochemical reaction as similar to HLM incubation. Additionally, in silico toxicity assessment of the detected transformation products of the analyzed substances was also evaluated.