title: 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.
authors.affiliation: National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.|Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
authors.forename: Roshan M
authors.initials: RM
authors.lastname: Borkar
authors.affiliation: National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
authors.forename: Murali Mohan
authors.initials: MM
authors.lastname: Bhandi
authors.affiliation: Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, 500037, India.
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Dubey
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
authors.forename: V
authors.initials: V
authors.lastname: Ganga Reddy
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, 500037, India.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Komirishetty
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar (Mohali), 160 062, Punjab, India.
authors.forename: Prajwal P
authors.initials: PP
authors.lastname: Nandekar
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar (Mohali), 160 062, Punjab, India.
authors.forename: Abhay T
authors.initials: AT
authors.lastname: Sangamwar
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.|Drug Discovery Research Center, Translational Health Science and Technology Institute, Faridabad, 121001, India.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Banerjee
authors.affiliation: National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.|Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, 500037, India.
authors.forename: R
authors.initials: R
authors.lastname: Srinivas
mesh_terms: D019540:Area Under Curve; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects*; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D008790:Metoprolol / Q000378:metabolism / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D008790:Metoprolol
keywords: CYP2D6; CYP3A4; drug-drug interaction; metoprolol metabolites