In vitrometabolism of monensin A: microbial and human liver microsomes models

Abstract

1. Monensin A, an important antibiotic ionophore that is primarily employed to treat coccidiosis, selectively complexes and transports sodium cations across lipid membranes and displays a variety of biological properties. 2. In this study, we evaluated the fungi Cunninghamella echinulata var. elegans ATCC 8688A, Cunninghamella elegans NRRL 1393 ATCC 10028B and human hepatic microsomes as CYP-P450 models to investigate the in vitro metabolism of monensin A and compare the products with the metabolites produced in vivo. 3. Mass spectrometry analysis of the products from these model systems revealed the formation of three metabolites: 3-O-demethyl monensin A, 12-hydroxy monensin A and 12-hydroxy-3-O-demethyl monensin A. We identified these products by tandem mass spectrometry and through comparison with the in vivo metabolites. 4. This analysis demonstrated that the model systems produce the same metabolites found in in vivo studies, thus they could be used to predict the metabolism of monensin A. Furthermore, we verified that liquid chromatography coupled to mass spectrometry is a powerful tool to study the in vitro metabolism of drugs, because it allows the successful identifications of several derivatives from different metabolic models.

Biotransformation of 4‐fluoro‐N‐(1‐{2‐[(propan‐2‐yl)phenoxy]ethyl}‐8‐azabicyclo[3.2.1]octan‐3‐yl)‐benzenesulfonamide, a novel potent 5‐HT7 receptor antagonist with antidepressant‐like and anxiolytic properties: In vitro and in silico approach

“…This is consistent with previous reports comparing xenobiotics biotransformation by Cunninghamella spp. and microsomes, which indicated that the generated metabolites are comparable . Moreover, our in silico data coincide with in vitro experiments, as three MetaSite metabolites of PZ‐1150 matched compounds identified in microsomal samples.…”

Jacobsen Catalyst as a Cytochrome P450 Biomimetic Model for the Metabolism of Monensin A

“…Additionally, products 1 and 2 displayed an identical low-resolution product ion spectrum (Supplementary Materials) as well as having the same retention times as those observed in the previous studies [21, 22]. The major ion formed in the MS/MS studies results from a Grob-Wharton type fragmentation and/or H 2 O, followed by CO elimination, as previously proposed for monensin A and its metabolites (Table 1) [21, 22, 28, 29]. …”

“…The analysis resulted in the [M + Na] + signal at m / z   679.4008 for product 1 (3- O -demethyl monensin A) and m / z   709,4134 for product 2 (12-hydroxy monensin A) confirming the molecular formula (mass error < 5 ppm) the same as observed for the products obtained from in vitro metabolism of monensin A by human liver microsomes and microbial transformation by fungi of Cunninghamella genus [21]. Additionally, products 1 and 2 displayed an identical low-resolution product ion spectrum (Supplementary Materials) as well as having the same retention times as those observed in the previous studies [21, 22]. The major ion formed in the MS/MS studies results from a Grob-Wharton type fragmentation and/or H 2 O, followed by CO elimination, as previously proposed for monensin A and its metabolites (Table 1) [21, 22, 28, 29].…”

Identification of metabolites of anticancer candidate salinomycin using liquid chromatography coupled with quadrupole time‐of‐flight and hybrid triple quadrupole linear ion trap mass spectrometry

“…In the case of complex biological matrices, high resolution may have an additional advantage of higher selectivity . However, when using in vitro models, the complexity of the sample is not that much of an issue and triple quadrupole or ion traps may be successfully applied …”