An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug–drug and drug–herb interaction by LC‐ESI/MS/MS

Abstract

The aim of the present study was to evaluate the contribution of metabolites to drug-drug interaction and drug-herb interaction using the inhibition of CYP2D6 and CYP3A4 by metoprolol (MET) and its metabolites. The peak concentrations of unbound plasma concentration of MET, α-hydroxy metoprolol (HM), O-desmethyl metoprolol (ODM) and N-desisopropyl metoprolol (DIM) were 90.37 ± 2.69, 33.32 ± 1.92, 16.93 ± 1.70 and 7.96 ± 0.94 ng/mL, respectively. The metabolites identified, HM and ODM, had a ratio of metabolic area under the concentration-time curve (AUC) to parent AUC of ≥0.25 when either total or unbound concentration of metabolite was considered. In vitro CYP2D6 and CYP3A4 inhibition by MET, HM and ODM study revealed that MET, HM and ODM were not inhibitors of CYP3A4-catalyzed midazolam metabolism and CYP2D6-catalyzed dextromethorphan metabolism. However, DIM only met the criteria of >10% of the total drug related material and <25% of the parent using unbound concentrations. If CYP inhibition testing is solely based on metabolite exposure, DIM metabolite would probably not be considered. However, the present study has demonstrated that DIM contributes significantly to in vitro drug-drug interaction. Copyright © 2016 John Wiley & Sons, Ltd.

Effects of Standardized Medicinal Plant Extracts on Drug Metabolism Mediated by CYP3A4 and CYP2D6 Enzymes

“…Table presents the data concerning the molar mass and retention times determined by UPLC-MS/MS for midazolam and metoprolol and their metabolites as well as their molecular formulas. These results are similar to those previously described in the literature. , …”

“…These results are similar to those previously described in the literature. 36,49 To select the drug substrate concentrations to be used for the evaluation of potential herb−drug interactions involving CYP3A4 and CYP2D6 recombinant enzymes, the substrate saturation curves were obtained for midazolam (Figure 1D) and metoprolol (Figure 1H). The kinetic parameters of drug metabolization in vitro (K m and V max ) are also displayed in Table 2.…”

“…29 The inhibition of this isoenzyme may lead to potential adverse interactions through the rapid increase of drug plasma levels leading to drug-induced toxicity. 34 Several studies report significant modulation of CYP enzymes by drugs, their metabolites, and natural products; 35,36 for instance, goldenseal (Hydrastis canadensis), liquorice (Glycyrrhiza glabra), valerian (Valeriana of f icinalis), 37 St. John's wort (Hypericum perforatum), 38,39 and medicinal plants used in Traditional Chinese Medicine. 40 Secondary metabolites, such as polyphenols 28,41,42 and alkaloids 43 are also described as CYP enzyme inhibitors.…”

Comparison between thaw-mounting and use of conductive tape for sample preparation in ToF-SIMS imaging of lipids in Drosophila microRNA-14 model

“…Currently, a number of advanced quantitative technologies-high-performance liquid chromatography, liquid chromatography tandem-mass spectrometry (LC-MS/MS), and liquid chromatography-electrospray ionization tandem-mass spectrometry (LC-ESI-MS/MS)-are being widely used as analysis methods in research on biological mechanisms. [1][2][3][4][5][6] However, although LC-MS is a highly sensitive and fast method for profiling compounds, it does not provide information on the spatial distribution of target analytes on the sample surface.…”