title: Donepezil plasma concentrations, CYP2D6 and CYP3A4 phenotypes, and cognitive outcome in Alzheimer's disease.
abstract: OBJECTIVE
  The purpose of the study is to evaluate whether donepezil (D) plasma concentrations and activity of CYP2D6 and CYP3A4 are associated with the therapeutic response of patients with mild to moderate Alzheimer's disease (AD).
  
  
  METHODS
  This study comprised 54 patients affected by probable AD in therapy with D 10 mg/daily for at least 3 months. Plasma concentrations of D and its three main metabolites (6DD, 5DD, DNox) were assayed with a novel high performance liquid chromatography (HPLC) technique. Cognitive progression was assessed at baseline and at 9 months of follow-up with the mini mental state examination (MMSE). The activities of the two cytochromes involved in D metabolism-CYP2D6 and CYP3A4-were evaluated according to their metabolic ratios in plasma or urine, after test doses of probe drugs (dextromethorphan and omeprazole).
  
  
  RESULTS
  A significant correlation was found between plasma levels of D and variations in MMSE scores after 9 months of therapy (r (2) = 0.14; p = 0.006). Neither the concentrations of D metabolites nor the metabolic ratios of CYP2D6 and CYP3A4 showed any correlations with cognitive variations. Low CYP2D6 activity and advanced age were associated with high D concentrations. Patients who were treated with CYP2D6 and P-glycoprotein (P-gp) inhibitors also had higher D plasma levels (mean difference = 19.6 ng/mL; p = 0.01) than those who were not.
  
  
  CONCLUSIONS
  D plasma concentrations, but not cytochrome phenotyping, are associated with cognitive outcomes in AD patients.
authors.affiliation: Geriatric Clinic, Department of Medicine DIMED, School of Medicine, University of Padova, 35128, Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Coin
authors.affiliation: Geriatric Clinic, Department of Medicine DIMED, School of Medicine, University of Padova, 35128, Padova, Italy.
authors.forename: M V
authors.initials: MV
authors.lastname: Pamio
authors.affiliation: Geriatric Clinic, Department of Medicine DIMED, School of Medicine, University of Padova, 35128, Padova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Alexopoulos
authors.affiliation: Geriatric Clinic, Department of Medicine DIMED, School of Medicine, University of Padova, 35128, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Granziera
authors.affiliation: Clinical Pharmacology Unit, Department of Medicine DIMED, School of Medicine, University of Padova, 35128, Padova, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Groppa
authors.affiliation: Clinical Pharmacology Unit, Department of Medicine DIMED, School of Medicine, University of Padova, 35128, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: de Rosa
authors.affiliation: Geriatric Clinic, Department of Medicine DIMED, School of Medicine, University of Padova, 35128, Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Girardi
authors.affiliation: Geriatric Clinic, Department of Medicine DIMED, School of Medicine, University of Padova, 35128, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sergi
authors.affiliation: Geriatric Clinic, Department of Medicine DIMED, School of Medicine, University of Padova, 35128, Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Manzato
authors.affiliation: Clinical Pharmacology Unit, Department of Medicine DIMED, School of Medicine, University of Padova, 35128, Padova, Italy. roberto.padrini@unipd.it.
authors.forename: R
authors.initials: R
authors.lastname: Padrini
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003071:Cognition; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D000077265:Donepezil; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007189:Indans / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D010641:Phenotype; D010880:Piperidines / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002800:Cholinesterase Inhibitors; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: Alzheimer disease; CYP2D6 phenotype; Donepezil; Plasma concentrations