title: Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A, ABCB1, POR and NR1I2 genotypes on donepezil clearance.
abstract: OBJECTIVE
  A large interindividual variability in plasma concentrations has been reported in patients treated with donepezil, the most frequently prescribed antidementia drug. We aimed to evaluate clinical and genetic factors influencing donepezil disposition in a patient population recruited from a naturalistic setting.
  
  
  METHODS
  A population pharmacokinetic study was performed including data from 129 older patients treated with donepezil. The patients were genotyped for common polymorphisms in the metabolic enzymes CYP2D6 and CYP3A, in the electron transferring protein POR and the nuclear factor NR1I2 involved in CYP activity and expression, and in the drug transporter ABCB1.
  
  
  RESULTS
  The average donepezil clearance was 7.3 l h(-1) with a 30% interindividual variability. Gender markedly influenced donepezil clearance (P < 0.01). Functional alleles of CYP2D6 were identified as unique significant genetic covariate for donepezil clearance (P < 0.01), with poor metabolizers and ultrarapid metabolizers demonstrating, respectively, a 32% slower and a 67% faster donepezil elimination compared with extensive metabolizers.
  
  
  CONCLUSIONS
  The pharmacokinetic parameters of donepezil were well described by the developed population model. Functional alleles of CYP2D6 significantly contributed to the variability in donepezil disposition in the patient population and should be further investigated in the context of individual dose optimization to improve clinical outcome and tolerability of the treatment.
authors.affiliation: Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Hospital of Cery, Lausanne University Hospital, Prilly, 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: Laurence
authors.initials: L
authors.lastname: Wilhelm
authors.forename: Agnès
authors.initials: A
authors.lastname: Michon
authors.forename: Valérie
authors.initials: V
authors.lastname: Thomazic
authors.forename: Ioana
authors.initials: I
authors.lastname: Stancu
authors.forename: Abdel-Messieh
authors.initials: AM
authors.lastname: Alnawaqil
authors.forename: Christophe
authors.initials: C
authors.lastname: Bula
authors.forename: Serge
authors.initials: S
authors.lastname: Zumbach
authors.forename: Michel
authors.initials: M
authors.lastname: Gaillard
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 / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D003430:Cross-Sectional Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D000077265:Donepezil; D005260:Female; D005838:Genotype; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D007189:Indans; C000625852:NR1I2 protein, human; D010880:Piperidines; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D000077265:Donepezil; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D009251:NADPH-Ferrihemoprotein Reductase
keywords: CYP2D6; CYP3A; NR1I2; POR; donepezil; population pharmacokinetics