title: Inhibitory effects of memantine on human cytochrome P450 activities: prediction of in vivo drug interactions.
abstract: OBJECTIVE
  The aim of the present study was to predict the drug interaction potential of memantine by elucidation of its inhibitory effects on cytochrome P450 enzymes using pooled human liver microsomes (HLM) and recombinant P450s.
  
  
  METHODS
  The inhibitory potency of memantine on CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 activities was examined with specific probe drugs in HLM and recombinant P450s. The in vivo drug interactions of memantine were predicted in vitro using the [ I]/([ I] + KI) values.
  
  
  RESULTS
  In HLM, memantine inhibited CYP2B6 and CYP2D6 activities, with KI (IC50) values of 76.7 (279.7) and 94.9 (368.7) microM, respectively. Both inhibitions were competitive. In addition, cDNA-expressed P450s were used to confirm these results. Memantine strongly inhibited recombinant CYP2B6 activity with IC50 ( KI) value of 1.12 (0.51) microM and activity of recombinant CYP2D6 with IC50 (KI) value of 242.4 (84.4) microM. With concentrations up to 1,000 microM, memantine showed no appreciable effect on CYP1A2, CYP2E1, CYP2C9, or CYP3A4 activities and a slight decrease of CYP2A6 and CYP2C19 activities. Based on [ I]/([ I] + KI) values calculated using peak total plasma concentration (or enzyme-available concentration in the liver) of memantine and the KI obtained in HLM, 1.3 (13.5), and 1.0% (11.2%), inhibition of the clearance of CYP2B6 and CYP2D6 substrates could be expected, respectively. Nevertheless, when considering KI values obtained from cDNA-expressed CYP2B6, as generally recommended, even 66.2% (95.9%) decrease in metabolism of coadministered CYP2B6 substrates could be anticipated.
  
  
  CONCLUSIONS
  Memantine exerts selective inhibition of CYP2B6 activity at clinically relevant concentrations, suggesting the potential for clinically significant drug interactions. Inhibition of other CYPs during memantine therapy is unlikely. Moreover, memantine represents a new, potent, selective inhibitor of recombinant CYP2B6, which may prove useful for screening purposes during early phases of in vitro drug metabolism studies with new chemical entities.
authors.affiliation: Department of Pharmacology, Medical Faculty of Charles University, Simkova 870, PO Box 38, 500 38, Hradec Kralove, Czech Republic. micuda@lfhk.cuni.cz
authors.forename: Stanislav
authors.initials: S
authors.lastname: Micuda
authors.forename: Lucie
authors.initials: L
authors.lastname: Mundlova
authors.forename: Eva
authors.initials: E
authors.lastname: Anzenbacherova
authors.forename: Pavel
authors.initials: P
authors.lastname: Anzenbacher
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Chladek
authors.forename: Leos
authors.initials: L
authors.lastname: Fuksa
authors.forename: Jirina
authors.initials: J
authors.lastname: Martinkova
mesh_terms: D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008559:Memantine / Q000008:administration & dosage / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects*
chemical_list: D000978:Antiparkinson Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D008559:Memantine