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Donepezil plasma concentrations, CYP2D6 and CYP3A4 phenotypes, and cognitive outcome in Alzheimer's disease.
- Source :
-
European journal of clinical pharmacology [Eur J Clin Pharmacol] 2016 Jun; Vol. 72 (6), pp. 711-7. Date of Electronic Publication: 2016 Mar 08. - Publication Year :
- 2016
-
Abstract
- Purpose: 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).<br />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).<br />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.<br />Conclusions: D plasma concentrations, but not cytochrome phenotyping, are associated with cognitive outcomes in AD patients.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors
Aged
Aged, 80 and over
Cholinesterase Inhibitors pharmacokinetics
Cholinesterase Inhibitors therapeutic use
Cytochrome P-450 CYP2D6 Inhibitors pharmacology
Donepezil
Drug Interactions
Female
Humans
Indans pharmacokinetics
Indans therapeutic use
Male
Phenotype
Piperidines pharmacokinetics
Piperidines therapeutic use
Alzheimer Disease blood
Alzheimer Disease drug therapy
Alzheimer Disease metabolism
Cholinesterase Inhibitors blood
Cognition
Cytochrome P-450 CYP2D6 metabolism
Cytochrome P-450 CYP3A metabolism
Indans blood
Piperidines blood
Subjects
Details
- Language :
- English
- ISSN :
- 1432-1041
- Volume :
- 72
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- European journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 26952092
- Full Text :
- https://doi.org/10.1007/s00228-016-2033-1