PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
donepezil

2D structure

Overview

IUPAC Name: 5,6-dimethoxy-2-[[1-(phenylmethyl)piperidin-4-yl]methyl]-2,3-dihydroinden-1-one
Trade Names: Aricept; Aricept ODT; Eranz
PharmGKB Accession Id: PA449394

Description

Donepezil (Aricept), is a centrally acting reversible acetyl cholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine. Donepezil is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. If this proposed mechanism of action is correct, donepezil's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. Donepezil has been tested in other cognitive disorders including Lewy body dementia and Vascular dementia, but it is not currently approved for these indications. Donepezil has also been studied in patients with Mild Cognitive Impairment, schizophrenia, attention deficit disorder, post-coronary bypass cognitive impairment, cognitive impairment associated with multiple sclerosis, and Down syndrome.

Indication

For management of symptoms associated with Alzheimer's Disease

ATC Therapeutic Category

  • N06DA:Anticholinesterases

Pharmacology and Interactions

Mechanism Of Action

Donepezil's proposed mechanism of action involves the increase of the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase.

Pharmacology

Donepezil is a centrally acting reversible acetyl cholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine. It is well absorbed in the gut with an oral bioavailability of 100% and easily crosses the blood-brain barrier. Because it has a half life of about 70 hours, it can be taken once a day. Initial dose is 5 mg per day, which can be increased to 10 mg per day after an adjustment period of at least 4 weeks. Donepezil is a parasympathomimetic, specifically, a reversible cholinesterase inhibitor. Donepezil is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. If this proposed mechanism of action is correct, donepezil's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that donepezil alters the course of the underlying dementing process.

Food Interactions

Avoid alcohol. Take without regard to meals.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 in the liver and also undergoes glucuronidation. The main metabolite, 6-O-desmethyl donepezil, has been reported to inhibit AChE to the same extent as donepezil in vitro.

Protein Binding

96%

Absorption

Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours.

Half Life

70 hours

Toxicity

Symptoms of overdose include severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.

Chemical Properties

Chemical Formula:

C24H29NO3

SMILES Code:

COc1cc2c(cc1OC)C(=O)C(C2)CC3CCN(CC3)Cc4ccccc4

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

379.492 / 379.2147

Curated Information

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
APOE
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  • PD
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Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
CHAT
  • CO
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  • GN
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No phenotype data Genotype Data Available Literature annotations available Not annotated
CYP1A2
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Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2D6
  • CO
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  • PK
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  • GN
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Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP3A
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  • PK
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Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A4
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  • PK
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Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A5
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  • PK
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No phenotype data No genotype data Literature annotations available Not annotated
SLC6A4
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  • PD
  • PK
  • FA
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Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other genes is available.

Metabolizing Enzymes

Drug Targets

Curated Information

The following drugs are in curated knowledge about this drug.

  Drug Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
carbamazepine
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Phenotype data available Genotype Data Available Literature annotations available Not annotated
ketoconazole
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No phenotype data No genotype data Literature annotations available Not annotated
oxcarbazepine
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  • PK
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Phenotype data available Genotype Data Available Literature annotations available Not annotated
phenobarbital
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Phenotype data available Genotype Data Available Literature annotations available Not annotated
phenytoin
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Phenotype data available Genotype Data Available Literature annotations available Not annotated
quinidine
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  • PK
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Phenotype data available Genotype Data Available Literature annotations available Not annotated
rifampin
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No phenotype data No genotype data Literature annotations available Not annotated
st. john's wort
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No phenotype data No genotype data Literature annotations available Not annotated
tacrine
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Non-Curated Information

A list of non-curated publications that mention this drug along with other drugs is available.

Drug Interactions

acepromazine Possible antagonism of action
aceprometazine Possible antagonism of action
alverine Possible antagonism of action
amantadine Possible antagonism of action
amitriptyline Possible antagonism of action
amoxapine Possible antagonism of action
atropine Possible antagonism of action
azatadine Possible antagonism of action
belladona Possible antagonism of action
benztropine Possible antagonism of action
biperiden Possible antagonism of action
brompheniramine Possible antagonism of action
carbinoxamine Possible antagonism of action
chlorpheniramine Possible antagonism of action
chlorpromazine Possible antagonism of action
chlorprothixene Possible antagonism of action
cimetidine Possible antagonism of action
clemastine Possible antagonism of action
clidinium Possible antagonism of action
clomipramine Possible antagonism of action
clozapine Possible antagonism of action
cyclizine Possible antagonism of action
cyclobenzaprine Possible antagonism of action
cyproheptadine Possible antagonism of action
darifenacin Possible antagonism of action
desipramine Possible antagonism of action
dexbrompheniramine Possible antagonism of action
dicyclomine Possible antagonism of action
dimenhydrinate Possible antagonism of action
diphenhydramine Possible antagonism of action
diphenoxylate Possible antagonism of action
diphenylpyraline Possible antagonism of action
disopyramide Possible antagonism of action
doxepin Possible antagonism of action
doxylamine Possible antagonism of action
ethopropazine Possible antagonism of action
flavoxate Possible antagonism of action
flupenthixol Possible antagonism of action
glutethimide Possible antagonism of action
glycopyrrolate Possible antagonism of action
hydroxyzine Possible antagonism of action
hyoscyamine Possible antagonism of action
imipramine Possible antagonism of action
isocarboxazid Possible antagonism of action
isopropamide Possible antagonism of action
loxapine Possible antagonism of action
maprotiline Possible antagonism of action
meclizine Possible antagonism of action
meperidine Possible antagonism of action
mesoridazine Possible antagonism of action
methdilazine Possible antagonism of action
methotrimeprazine Possible antagonism of action
methylscopolamine Possible antagonism of action
mirtazapine Possible antagonism of action
moclobemide Possible antagonism of action
molindone Possible antagonism of action
nortriptyline Possible antagonism of action
olanzapine Possible antagonism of action
orphenadrine Possible antagonism of action
oxybutynin Possible antagonism of action
perphenazine Possible antagonism of action
phenelzine Possible antagonism of action
phenindamine Possible antagonism of action
pheniramine Possible antagonism of action
pimozide Possible antagonism of action
pipotiazine Possible antagonism of action
procainamide Possible antagonism of action
prochlorperazine Possible antagonism of action
procyclidine Possible antagonism of action
promazine Possible antagonism of action
promethazine Possible antagonism of action
propantheline Possible antagonism of action
propericiazine Possible antagonism of action
protriptyline Possible antagonism of action
quetiapine Possible antagonism of action
quinidine Possible antagonism of action
quinidine barbiturate Possible antagonism of action
risperidone Possible antagonism of action
scopolamine Possible antagonism of action
scopolamine Possible antagonism of action
sertraline Possible antagonism of action
solifenacin Possible antagonism of action
thioproperazine Possible antagonism of action
thioridazine Possible antagonism of action
thiothixene Possible antagonism of action
tizanidine Possible antagonism of action
tolterodine Possible antagonism of action
tranylcypromine Possible antagonism of action
trazodone Possible antagonism of action
trifluoperazine Possible antagonism of action
triflupromazine Possible antagonism of action
trihexyphenidyl Possible antagonism of action
trimeprazine Possible antagonism of action
trimethobenzamide Possible antagonism of action
trimipramine Possible antagonism of action
tripelennamine Possible antagonism of action
triprolidine Possible antagonism of action
trospium Possible antagonism of action
ziprasidone Possible antagonism of action
zuclopenthixol Possible antagonism of action

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
Alzheimer Disease
  • CO
  • PD
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  • FA
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Atrial Fibrillation
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No phenotype data No genotype data Literature annotations available Not annotated
Dementia
  • CO
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No phenotype data No genotype data Literature annotations available Not annotated
Neurodegenerative Diseases
  • CO
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Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00843
KEGG Drug ID:
D00670
PubChem Compound ID:
3152
PubChem Substance ID:
207105

Common Searches

Search PubMed
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Non-Curated Publications

A list of non-curated publications that mention this drug is available.

PharmGKB integrates drug information from different sources: DrugBank, Open Eye Scientific Software.
The PharmGKB is financially supported by the NIH/ NIGMS and is managed at Stanford University (U01GM61374).
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