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. (19th April 2016)

• Record Type: Journal Article
• Authors: Borkar, Roshan M.; Bhandi, Murali Mohan; Dubey, Ajay P.; Ganga Reddy, V.; Komirishetty, Prashanth; Nandekar, Prajwal P.; Sangamwar, Abhay T.; Kamal, Ahmed; Banerjee, Sanjay K.; Srinivas, R.
• Is Part Of: Biomedical chromatography. Volume 30:Number 10(2016:Oct.)
• Page Start: 1556
• Page End: 1572
• Publication Date: 2016-04-19
• Subjects: metoprolol metabolites -- CYP2D6 -- CYP3A4 -- drug–drug interaction; Chromatographic analysis -- Periodicals; Biology -- Periodicals; Medicine -- Periodicals; Biology -- Periodicals; Chromatography -- methods -- Periodicals; Medicine -- Periodicals; 543.089
• DOI: 10.1002/bmc.3721
• Languages: English
• ISSNs: 0269-3879

Abstract

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.