title: Relationship of CYP2D6, CYP3A, POR, and ABCB1 genotypes with galantamine plasma concentrations.
abstract: BACKGROUND
  The frequently prescribed antidementia drug galantamine is extensively metabolized by the enzymes cytochrome P450 (CYP) 2D6 and CYP3A and is a substrate of the P-glycoprotein. We aimed to study the relationship between genetic variants influencing the activity of these enzymes and transporters with galantamine steady state plasma concentrations.
  
  
  METHODS
  In this naturalistic cross-sectional study, 27 older patients treated with galantamine were included. The patients were genotyped for common polymorphisms in CYP2D6, CYP3A4/5, POR, and ABCB1, and galantamine steady state plasma concentrations were determined.
  
  
  RESULTS
  The CYP2D6 genotype seemed to be an important determinant of galantamine pharmacokinetics, with CYP2D6 poor metabolizers presenting 45% and 61% higher dose-adjusted galantamine plasma concentrations than heterozygous and homozygous CYP2D6 extensive metabolizers (median 2.9 versus 2.0 ng/mL · mg, P = 0.025, and 1.8 ng/mL · mg, P = 0.004), respectively.
  
  
  CONCLUSIONS
  The CYP2D6 genotype significantly influenced galantamine plasma concentrations. The influence of CYP2D6 polymorphisms on the treatment efficacy and tolerability should be further investigated.
authors.affiliation: Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, University Hospital Lausanne, Prilly-Lausanne, Switzerland.
authors.forename: Muriel
authors.initials: M
authors.lastname: Noetzli
authors.forename: Monia
authors.initials: M
authors.lastname: Guidi
authors.forename: Karsten
authors.initials: K
authors.lastname: Ebbing
authors.forename: Stephan
authors.initials: S
authors.lastname: Eyer
authors.forename: Serge
authors.initials: S
authors.lastname: Zumbach
authors.forename: Panteleimon
authors.initials: P
authors.lastname: Giannakopoulos
authors.forename: Armin
authors.initials: A
authors.lastname: von Gunten
authors.forename: Chantal
authors.initials: C
authors.lastname: Csajka
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D002800:Cholinesterase Inhibitors / Q000097:blood; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003704:Dementia / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D005260:Female; D005702:Galantamine / Q000097:blood* / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002800:Cholinesterase Inhibitors; D005702:Galantamine; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D009251:NADPH-Ferrihemoprotein Reductase