Donepezil

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Identification

Summary

Donepezil is an acetylcholinesterase inhibitor used to treat the behavioral and cognitive effects of Alzheimer's Disease and other types of dementia.

Brand Names

Adlarity, Aricept, Namzaric

Generic Name

Donepezil

DrugBank Accession Number

DB00843

Background

In 2016, the global burden of dementia was estimated to be 43.8 million, demonstrating a significant increase from a global prevalence of 20.2 million in 1990.¹⁶ Donepezil, also known as Aricept, is a piperidine derivative acetylcholinesterase inhibitor used in the management of the dementia of Alzheimer's Disease, and in some cases, is used to manage other types of dementia.

Donepezil was first approved by the FDA in 1996, and its extended-release form was approved in combination with Memantine in 2014 to manage moderate and severe forms of Alzheimer's dementia.^19,22 A donepezil transdermal delivery system, Adlarity, was approved by the FDA in March 2022 for the treatment of Alzheimer's dementia.²⁴ Though it does not alter the progression of Alzheimer's disease, donepezil is effective in managing the symptoms of its associated dementia.¹⁸

Type

Small Molecule

Groups

Approved

Structure

Similar Structures

Weight: Average: 379.492
Monoisotopic: 379.214743799
Chemical Formula: C₂₄H₂₉NO₃

Synonyms

Domepezil
Donepezil
Donepezilo
Donepezilum

External IDs

BNAG
E 2020

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Pharmacology

Indication

Donepezil, administered orally¹⁹ or via transdermal delivery system,²⁴ is indicated for the treatment of dementia of the Alzheimer's type. It is also available as an extended-release capsule in combination with memantine for the treatment of moderate-to-severe dementia of the Alzheimer's type in patients previously stabilized on 10mg of donepezil hydrochloride once daily.²²

Off-label uses include the management of vascular dementia, Parkinson's Disease-associated dementia, and Lewy body dementia, amongst others.^8,18

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Dose Form
Used in combination to manage	Alzheimer's disease (ad)	Combination Product in combination with: Ginkgo biloba (DB01381), Memantine (DB01043)	••••••••••••	•••••• •••••••	••••••• ••••••••••••
Management of	Dementia due to parkinson's disease		••• •••••
Treatment of	Dementia of the alzheimer's type		••••••••••••		•••••
Treatment of	Dementia of the alzheimer's type		••••••••••••		••••••• ••••••• •••••• ••••••••••••••
Used in combination to manage	Dementia of the alzheimer's type	Combination Product in combination with: Ginkgo biloba (DB01381)	••••••••••••	•••••• •••••••	••••••• ••••••••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

By inhibiting the acetylcholinesterase enzyme, donepezil improves the cognitive and behavioral signs and symptoms of Alzheimer's Disease, which may include apathy, aggression, confusion, and psychosis.^8,15

Mechanism of action

The commonly accepted cholinergic hypothesis¹³ proposes that a portion of the cognitive and behavioral decline associated with Alzheimer's are the result of decreased cholinergic transmission in the central nervous system. Donepezil selectively and reversibly inhibits the acetylcholinesterase enzyme, which normally breaks down acetylcholine. The main pharmacological actions of this drug are believed to occur as the result of this enzyme inhibition, enhancing cholinergic transmission, which relieves the symptoms of Alzheimer's dementia. In addition to the above, other mechanisms of action of donepezil are possible, including the opposition of glutamate-induced excitatory transmission via downregulation of NMDA receptors and the regulation of amyloid proteins, which have demonstrated significant effects on the disease process of Alzheimer's.^8,12,17 Other possible targets for donepezil may also include the inhibition various inflammatory signaling pathways, exerting neuroprotective effects.^10,14

Target	Actions	Organism
AAcetylcholinesterase	inhibitor	Humans
U5-hydroxytryptamine receptor 2A	inducer	Humans
UCholinesterase	inducer	Humans
UNitric oxide synthase 1	inhibitor inducer	Humans
UTumor necrosis factor-inducible gene 6 protein	inhibitor	Humans
UInterleukin-1 beta	inhibitor inducer	Humans
UNuclear factor NF-kappa-B	inhibitor	Humans
UNMDA receptor	downregulator	Humans

Absorption

Donepezil is slowly absorbed via the gastrointestinal tract after oral administration. Tmax is 3 to 4 hours with a bioavailability of 100% and steady-state concentrations are attained within 15 to 21 days of administration.⁸ The Tmax in one pharmacokinetic study determined a Tmax of 4.1 ± 1.5 hours.⁶ The Cmax of 5 mg donepezil tablets is estimated to be 8.34 ng/mL, according to the Canadian monograph.²³ The AUC of 5 mg donepezil tablets has been determined to be 221.90-225.36 ng.hr/mL.²³

Volume of distribution

The volume of distribution of donepezil is 11.8 ± 1.7 L/kg for a 5-mg dose and 11.6 ± 1.91 L/kg for a 10-mg dose. It is largely distributed in the extravascular compartments. Donepezil crosses the blood-brain barrier and cerebrospinal fluid concentrations at the above doses have been measured at 15.7%.⁸ The volume of distribution at steady-state according to the FDA label for donepezil ranges from 12 - 16 L/kg.¹⁹

Protein binding

Donepezil is 96% protein-bound, with approximately 75% binding to albumin and approximately 21% binding to alpha-1-glycoprotein.^8,23

Metabolism

Donepezil is metabolized by first pass metabolism in the liver, primarily by CYP3A4, in addition to CYP2D6. After this, O-dealkylation, hydroxylation, N-oxidation, hydrolysis, and O-glucuronidation occur, producing various metabolites with similar half-lives to the unchanged parent drug. A study of the pharmacokinetics of radiolabeled donepezil demonstrated that about 53% of plasma radioactivity appeared as donepezil in the unchanged form, and 11% was identified as the metabolite 6-O-desmethyl donepezil, which exerts similar potency inhibition of the acetylcholinesterase enzyme.^8,19 This drug is heavily metabolized to four primary metabolites, two of which are considered pharmacologically active, as well as to multiple inactive and unidentified metabolites.¹⁹

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Donepezil

Route of elimination

In a study of radiolabeled administration donepezil in healthy adults, 57% of measured radioactivity was identified in the urine, and 5% was identified in the feces.⁸

Half-life

The average elimination half-life of donepezil is about 70 hours according to the results of various studies and the FDA label for donepezil.^8,19. One pharmacokinetic study determined the average terminal half-life to be 81.5±22.0 h⁶

Clearance

According to the FDA label, the average apparent plasma clearance of this drug is 0.13 – 0.19 L/hr/kg.¹⁹ A 5 mg dose of donepezil in healthy patients was shown to have a plasma clearance of 0.110±0.02 L/h/kg.²³ In 10 patients diagnosed with alcoholic cirrhosis, showed a mean decrease in clearance by 20% when compared to the clearance in 10 healthy subjects. In 4 patients with severe renal impairment compared to 4 healthy subjects, no significant change in clearance was noted.²³

Adverse Effects

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Toxicity

LD50

The rat oral LD50 of donepezil is 32.6 mg/kg.²¹

Overdose information

Signs and symptoms of overdose with cholinesterase inhibitors such as donepezil can include severe nausea and vomiting, bradycardia, hypotension, perspiration, seizures, muscle weakness respiratory depression, and collapse. Significant muscle weakness may result in death if the respiratory muscles are affected by donepezil overdose. To manage an overdose, anticholinergics can be employed as antidotes. Atropine at intravenous doses of 1.0 - 2.0 mg can be administered and titrated according to the clinical response. Consult the local poison control center for the most updated guidelines on the management of a donepezil overdose. Whether donepezil can be removed from the body with dialysis is unknown at this time.¹⁹

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Interacting Gene/Enzyme	Allele name	Genotype(s)	Defining Change(s)	Type(s)	Description	Details
Cytochrome P450 2D6	CYP2D6*2A	(G;G) / (C;G)	C > G	Effect Directly Studied	Patients with this genotype are have a decreased likelihood of responding to donepezil when treating Alzheimer's disease.	Details

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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1,2-Benzodiazepine	The risk or severity of CNS depression can be increased when Donepezil is combined with 1,2-Benzodiazepine.
Abametapir	The serum concentration of Donepezil can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Donepezil can be increased when combined with Abatacept.
Abemaciclib	Abemaciclib may decrease the excretion rate of Donepezil which could result in a higher serum level.
Abiraterone	The metabolism of Donepezil can be decreased when combined with Abiraterone.

Food Interactions

Avoid alcohol.
Take with or without food. The absorption is unaffected by food.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Donepezil hydrochloride	3O2T2PJ89D	120011-70-3	XWAIAVWHZJNZQQ-UHFFFAOYSA-N
Donepezil hydrochloride monohydrate	7KZL5YRL6W	884740-09-4	HLJIZAKUNCTCQX-UHFFFAOYSA-N

Product Images

International/Other Brands

Alzepil (Egis) / Davia (Terapia) / Depzil (Psyco Remedies) / Donecept (Actavis) / Donecil (ABL Pharma) / Donep (Alkem) / Donepex (Schafer) / Donesyn (Synthon) / Dopezil (Medis) / Eranz (Wyeth) / Memac (Pfizer) / Nomi-Nox (Johnson) / Pezale (Sandoz) / Redumas (Teva) / Zolpezil (Actavis)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Act Donepezil	Tablet	10 mg	Oral	Actavis Pharma Company	2013-12-27	2018-06-12
Act Donepezil	Tablet	5 mg	Oral	Actavis Pharma Company	2013-12-27	2018-06-12
Act Donepezil ODT	Tablet, orally disintegrating	5 mg	Oral	Teva Italia S.R.L.	2013-12-27	2022-05-30
Act Donepezil ODT	Tablet, orally disintegrating	10 mg	Oral	Teva Italia S.R.L.	2013-12-27	2022-05-30
Adlarity	Patch	5 mg/1	Transdermal	Corium, LLC.	2022-03-11	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Accel-donepezil	Tablet	5 mg	Oral	Accel Pharma Inc	2014-09-04	2019-10-28
Accel-donepezil	Tablet	10 mg	Oral	Accel Pharma Inc	2014-09-04	2019-10-28
Ach-donepezil	Tablet	10 mg	Oral	Accord Healthcare, S.L.U.	2013-12-27	Not applicable
Ach-donepezil	Tablet	5 mg	Oral	Accord Healthcare, S.L.U.	2013-12-27	Not applicable
Ag-donepezil	Tablet	10 mg	Oral	Angita Pharma Inc.	2021-05-10	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
BERMAXIN 90/10/5 MG FILM TABLET ,FILM TABLET, 28 ADET	Donepezil hydrochloride (10 mg) + Idebenone (90 mg) + Memantine hydrochloride (5 mg)	Tablet, film coated	Oral	CELTİS İLAÇ SAN. VE TİC. A.Ş.	2014-03-31	Not applicable
BERMAXIN 90/10/5 MG FILM TABLET ,FILM TABLET, 84 ADET	Donepezil hydrochloride (10 mg) + Idebenone (90 mg) + Memantine hydrochloride (5 mg)	Tablet, film coated	Oral	CELTİS İLAÇ SAN. VE TİC. A.Ş.	2014-03-31	Not applicable
DEMENT COMBİ 10 MG / 10 MG AĞIZDA DAĞILAN TABLET, 28 TABLET	Donepezil hydrochloride (10 mg) + Memantine hydrochloride (10 mg)	Tablet, orally disintegrating	Oral	ALİ RAİF İLAÇ SAN. A.Ş.	2020-08-14	Not applicable
DEMENT COMBİ 10 MG / 10 MG AĞIZDA DAĞILAN TABLET, 7 TABLET	Donepezil hydrochloride (10 mg) + Memantine hydrochloride (10 mg)	Tablet, orally disintegrating	Oral	ALİ RAİF İLAÇ SAN. A.Ş.	2020-08-14	Not applicable
DEMENT COMBİ 10 MG / 15 MG AĞIZDA DAĞILAN TABLET, 7 TABLET	Donepezil hydrochloride (10 mg) + Memantine hydrochloride (15 mg)	Tablet, orally disintegrating	Oral	ALİ RAİF İLAÇ SAN. A.Ş.	2020-08-14	Not applicable

Unapproved/Other Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Donepezil Hydrochloride	Donepezil hydrochloride (10 mg/1)	Tablet, film coated	Oral	Teva Italia S.R.L.	2011-04-14	2011-04-14
Donepezil Hydrochloride	Donepezil hydrochloride (5 mg/1)	Tablet, film coated	Oral	Teva Italia S.R.L.	2011-04-14	2011-04-14

Chemical Identifiers

UNII: 8SSC91326P
CAS number: 120014-06-4
InChI Key: ADEBPBSSDYVVLD-UHFFFAOYSA-N
InChI: InChI=1S/C24H29NO3/c1-27-22-14-19-13-20(24(26)21(19)15-23(22)28-2)12-17-8-10-25(11-9-17)16-18-6-4-3-5-7-18/h3-7,14-15,17,20H,8-13,16H2,1-2H3
IUPAC Name: 2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one
SMILES: COC1=C(OC)C=C2C(=O)C(CC3CCN(CC4=CC=CC=C4)CC3)CC2=C1

References

Synthesis Reference

Akio Imai, Hideaki Watanabe, Takashi Kajima, Yasushi Ishihama, Akiyo Ohtsuka, Tomohide Tanaka, Yukio Narabu, "Polymorphs of donepezil hydrochloride and process for production." U.S. Patent US5985864, issued December, 1988.

US5985864

General References

Xiong G, Doraiswamy PM: Combination drug therapy for Alzheimer's disease: what is evidence-based, and what is not? Geriatrics. 2005 Jun;60(6):22-6. [Article]
Yesavage JA, Mumenthaler MS, Taylor JL, Friedman L, O'Hara R, Sheikh J, Tinklenberg J, Whitehouse PJ: Donepezil and flight simulator performance: effects on retention of complex skills. Neurology. 2002 Jul 9;59(1):123-5. [Article]
Sugimoto H: Donepezil hydrochloride: a treatment drug for Alzheimer's disease. Chem Rec. 2001;1(1):63-73. [Article]
Korabecny J, Spilovska K, Mezeiova E, Benek O, Juza R, Kaping D, Soukup O: A systematic review on donepezil-based derivatives as potential cholinesterase inhibitors for Alzheimer's disease. Curr Med Chem. 2018 May 16. pii: CMC-EPUB-90497. doi: 10.2174/0929867325666180517094023. [Article]
Prvulovic D, Schneider B: Pharmacokinetic and pharmacodynamic evaluation of donepezil for the treatment of Alzheimer's disease. Expert Opin Drug Metab Toxicol. 2014 Jul;10(7):1039-50. doi: 10.1517/17425255.2014.915028. Epub 2014 Apr 30. [Article]
Rogers SL, Friedhoff LT: Pharmacokinetic and pharmacodynamic profile of donepezil HCl following single oral doses. Br J Clin Pharmacol. 1998 Nov;46 Suppl 1:1-6. doi: 10.1046/j.1365-2125.1998.0460s1001.x. [Article]
Tiseo PJ, Perdomo CA, Friedhoff LT: Metabolism and elimination of 14C-donepezil in healthy volunteers: a single-dose study. Br J Clin Pharmacol. 1998 Nov;46 Suppl 1:19-24. doi: 10.1046/j.1365-2125.1998.0460s1019.x. [Article]
Seltzer B: Donepezil: a review. Expert Opin Drug Metab Toxicol. 2005 Oct;1(3):527-36. doi: 10.1517/17425255.1.3.527 . [Article]
Hughes RE, Nikolic K, Ramsay RR: One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug. Front Neurosci. 2016 Apr 25;10:177. doi: 10.3389/fnins.2016.00177. eCollection 2016. [Article]
Hwang J, Hwang H, Lee HW, Suk K: Microglia signaling as a target of donepezil. Neuropharmacology. 2010 Jun;58(7):1122-9. doi: 10.1016/j.neuropharm.2010.02.003. Epub 2010 Feb 11. [Article]
Owen RT: Memantine and donepezil: a fixed drug combination for the treatment of moderate to severe Alzheimer's dementia. Drugs Today (Barc). 2016 Apr;52(4):239-48. doi: 10.1358/dot.2016.52.4.2479357. [Article]
Murphy MP, LeVine H 3rd: Alzheimer's disease and the amyloid-beta peptide. J Alzheimers Dis. 2010;19(1):311-23. doi: 10.3233/JAD-2010-1221. [Article]
Terry AV Jr, Buccafusco JJ: The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther. 2003 Sep;306(3):821-7. doi: 10.1124/jpet.102.041616. Epub 2003 Jun 12. [Article]
Srinivasan M, Lahiri DK: Significance of NF-kappaB as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer's disease and multiple sclerosis. Expert Opin Ther Targets. 2015 Apr;19(4):471-87. doi: 10.1517/14728222.2014.989834. Epub 2015 Feb 4. [Article]
Li XL, Hu N, Tan MS, Yu JT, Tan L: Behavioral and psychological symptoms in Alzheimer's disease. Biomed Res Int. 2014;2014:927804. doi: 10.1155/2014/927804. Epub 2014 Jul 15. [Article]
Authors unspecified: Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019 Jan;18(1):88-106. doi: 10.1016/S1474-4422(18)30403-4. Epub 2018 Nov 26. [Article]
Shen H, Kihara T, Hongo H, Wu X, Kem WR, Shimohama S, Akaike A, Niidome T, Sugimoto H: Neuroprotection by donepezil against glutamate excitotoxicity involves stimulation of alpha7 nicotinic receptors and internalization of NMDA receptors. Br J Pharmacol. 2010 Sep;161(1):127-39. doi: 10.1111/j.1476-5381.2010.00894.x. [Article]
Anil Kumar; Sandeep Sharma (2019). Donepezil. Stat Pearls.
FDA Approved Drug Products: Aricept/Aricept ODT (donepezil hydrochloride) tablets for oral use [Link]
Australian monograph, Donepezil [Link]
Pfizer MSDS, Donepezil hydrochloride [Link]
FDA Approved Drug Products: Namzaric (memantine hydrochloride and donepezil hydrochloride) extended-release capsules for oral use [Link]
Pfizer monograph, donepezil [Link]
FDA Approved Drug Products: Adlarity (donepezil) transdermal system [Link]

External Links

Human Metabolome Database: HMDB0005041
KEGG Drug: D00670
PubChem Compound: 3152
PubChem Substance: 46504803
ChemSpider: 3040
BindingDB: 8960
RxNav: 135447
ChEBI: 145499
ChEMBL: CHEMBL502
Therapeutic Targets Database: DAP000560
PharmGKB: PA449394
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Donepezil

MSDS

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Clinical Trials

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Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
Not Available	Completed	Not Available	Alzheimer's Disease (AD)	6	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Alzheimer's Disease (AD) / Dementia	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Alzheimer's Disease (AD) / Vascular Dementia (VaD)	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Biomarkers, Pharmacological	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Cholinergic Function	1	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Eisai inc
Mutual pharmaceutical co inc
Teva pharmaceuticals usa inc

Packagers

Amerisource Health Services Corp.
AQ Pharmaceuticals Inc.
Bryant Ranch Prepack
Cardinal Health
DispenseXpress Inc.
Eisai Inc.
Greenstone LLC
Lake Erie Medical and Surgical Supply
Murfreesboro Pharmaceutical Nursing Supply
PD-Rx Pharmaceuticals Inc.
Pfizer Inc.
Physicians Total Care Inc.
Prepackage Specialists
Prepak Systems Inc.
Resource Optimization and Innovation LLC
Vangard Labs Inc.

Dosage Forms

Form	Route	Strength
Patch	Transdermal	10 mg/1
Patch	Transdermal	5 mg/1
Tablet, orally disintegrating	Oral	10 mg
Tablet, orally disintegrating	Oral	5 mg
Tablet, film coated	Oral	5.000 mg
Solution	Oral	1 mg/1mL
Tablet, coated	Oral	4.56 MG
Tablet, coated	Oral	9.12 MG
Tablet, film coated	Oral	10 mg
Tablet, coated	Oral	5 mg
Tablet, soluble	Oral	10 mg
Tablet, soluble	Oral	5 MG
Tablet, film coated	Oral	23 mg
Tablet, coated	Oral	1000000 mg
Tablet, orally disintegrating	Oral
Kit; tablet, orally disintegrating	Oral
Tablet, film coated, extended release	Oral
Tablet, effervescent
Tablet, orally disintegrating	Oral
Tablet, film coated	Oral
Tablet	Oral	10 mg/1
Tablet	Oral	23 mg/1
Tablet	Oral	5 mg/1
Tablet, extended release	Oral	23 mg/1
Tablet, film coated	Oral	10 mg/1
Tablet, film coated	Oral	23 mg/1
Tablet, film coated	Oral	5 mg/1
Tablet, orally disintegrating	Oral	10 mg/1
Tablet, orally disintegrating	Oral	5 mg/1
Tablet, film coated	Oral	5217 MG
Tablet	Oral	3 mg
Tablet, orally disintegrating	Oral	9.12 MG
Film	Oral
Tablet, orally disintegrating	Oral	10.0 mg
Tablet, orally disintegrating	Oral	5.0 mg
Tablet, coated	Oral
Tablet, film coated	Oral	10.00 mg
Tablet, film coated	Oral	5.00 mg
Tablet	Oral	5.000 mg
Tablet, effervescent	Oral
Capsule	Oral	14.000 mg
Tablet	Oral	10 mg
Tablet	Oral	5 mg
Tablet	Oral	10.000 mg
Tablet	Oral
Capsule, extended release	Oral
Capsule	Oral
Kit	Oral
Tablet	Oral	10.000 mg
Tablet, film coated	Oral
Kit; tablet, film coated	Oral
Tablet	Oral
Tablet, effervescent
Tablet, coated
Tablet	Oral	5.00 mg
Tablet, extended release	Oral	23 mg
Tablet, film coated	Oral	5 mg
Tablet, coated	Oral	10 mg

Prices

Unit description	Cost	Unit
Aricept ODT 30 5 mg Dispersible Tablet Box	272.99USD	box
Aricept 10 mg tablet	10.93USD	tablet
Aricept 5 mg tablet	9.78USD	tablet
Aricept odt 10 mg tablet	8.03USD	tablet
Aricept odt 5 mg tablet	8.03USD	tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US4895841	No	1990-01-23	2010-11-25
CA2252806	No	2005-11-22	2017-06-06
CA1338808	No	1996-12-24	2013-12-24
US7727548	No	2010-06-01	2022-06-23
US7727552	No	2010-06-01	2018-03-26
US8173708	Yes	2012-05-08	2026-05-22
US8283379	Yes	2012-10-09	2026-05-22
US8362085	Yes	2013-01-29	2026-05-22
US8039009	Yes	2011-10-18	2029-09-24
US8329752	Yes	2012-12-11	2026-05-22
US8598233	Yes	2013-12-03	2026-05-22
US8168209	Yes	2012-05-01	2026-05-22
US8481565	No	2013-07-09	2026-10-04
US8338486	No	2012-12-25	2025-11-22
US8058291	No	2011-11-15	2029-12-05
US8580858	No	2013-11-12	2025-11-22
US8338485	No	2012-12-25	2025-11-22
US8293794	No	2012-10-23	2025-11-22
US5061703	Yes	1991-10-29	2015-10-11
US10966936	No	2021-04-06	2038-08-11
US11103463	No	2021-08-31	2037-07-26
US10835499	No	2020-11-17	2038-05-20
US10016372	No	2018-07-10	2037-07-26
US10307379	No	2019-06-04	2037-07-26
US9993466	No	2018-06-12	2037-07-26
US10300025	No	2019-05-28	2037-07-26
US11648214	No	2017-09-23	2037-09-23
US11679086	No	2017-05-26	2037-05-26

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	223-227	https://aksci.com/item_detail.php?cat=J10827
boiling point (°C)	527.9	https://www.lookchem.com/Donepezil-hydrochloride/
water solubility	31mg/mL	https://aksci.com/item_detail.php?cat=J10827
logP	4.7	https://www.sunpharma.com/australia-pi-download/50508/Donepezil
pKa	8.9	https://www.sunpharma.com/australia-pi-download/50508/Donepezil

Predicted Properties

Property	Value	Source
Water Solubility	0.0045 mg/mL	ALOGPS
logP	4.14	ALOGPS
logP	4.21	Chemaxon
logS	-4.9	ALOGPS
pKa (Strongest Acidic)	16.78	Chemaxon
pKa (Strongest Basic)	9.12	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	38.77 Å²	Chemaxon
Rotatable Bond Count	6	Chemaxon
Refractivity	112.11 m³·mol^-1	Chemaxon
Polarizability	44.34 Å³	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	Yes	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9966
Blood Brain Barrier	+	0.9953
Caco-2 permeable	+	0.7742
P-glycoprotein substrate	Substrate	0.7721
P-glycoprotein inhibitor I	Inhibitor	0.7641
P-glycoprotein inhibitor II	Inhibitor	0.8202
Renal organic cation transporter	Inhibitor	0.7696
CYP450 2C9 substrate	Non-substrate	0.8465
CYP450 2D6 substrate	Substrate	0.8919
CYP450 3A4 substrate	Substrate	0.7202
CYP450 1A2 substrate	Inhibitor	0.5072
CYP450 2C9 inhibitor	Non-inhibitor	0.8189
CYP450 2D6 inhibitor	Inhibitor	0.8684
CYP450 2C19 inhibitor	Non-inhibitor	0.8356
CYP450 3A4 inhibitor	Non-inhibitor	0.7411
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.6138
Ames test	Non AMES toxic	0.6441
Carcinogenicity	Non-carcinogens	0.9528
Biodegradation	Not ready biodegradable	0.9145
Rat acute toxicity	3.0123 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Strong inhibitor	0.5386
hERG inhibition (predictor II)	Inhibitor	0.8095

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-0fdo-6948000000-6c7dc19cab1af35fbb59
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-001i-0009000000-1e37ddb4068d0265fe2d
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-0009000000-2bd67b7ed0fce1714eca
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-001i-1019000000-dc6f071ec8b46790ee6d
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-0009000000-0412ed9a1ccd4915ac96
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-001l-5089000000-d56082413067db60b3ef
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0fh9-0039000000-a4052a58adfe4af59b00
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	221.0285277	predicted	DarkChem Lite v0.1.0
[M-H]-	193.5253	predicted	DeepCCS 1.0 (2019)
[M+H]+	220.8982277	predicted	DarkChem Lite v0.1.0
[M+H]+	195.88329	predicted	DeepCCS 1.0 (2019)
[M+Na]+	219.5514277	predicted	DarkChem Lite v0.1.0
[M+Na]+	202.72862	predicted	DeepCCS 1.0 (2019)

Targets

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Property	Measurement	pH	Temperature (°C)	References
EC 50 (nM)	43	N/A	N/A	A29125
IC 50 (nM)	8	N/A	N/A	A27970 / A27971 / A27972 / A29124 / A28009
IC 50 (nM)	12	N/A	N/A	A29124
IC 50 (nM)	17	N/A	N/A	A29124
IC 50 (nM)	16	N/A	N/A	A16781 / A27979
IC 50 (nM)	40	N/A	N/A	A27980
IC 50 (nM)	22	8	37	A27981 / A27991
IC 50 (nM)	18	N/A	N/A	A29125 / A28015
IC 50 (nM)	23.1	8	37	A29126
IC 50 (nM)	22	N/A	N/A	A27987 / A28017
IC 50 (nM)	23.1	N/A	N/A	A27996 / A28783
IC 50 (nM)	23	N/A	N/A	A27999 / A29133
IC 50 (nM)	160	N/A	N/A	A29128
IC 50 (nM)	20	N/A	N/A	A29129 / A29130
IC 50 (nM)	>100000	N/A	N/A	A29131
IC 50 (nM)	8.2	N/A	N/A	A28011
IC 50 (nM)	90	N/A	N/A	A28012
IC 50 (nM)	120	N/A	N/A	A29132
IC 50 (nM)	6	N/A	N/A	A28014
IC 50 (nM)	4150	N/A	N/A	A28017
IC 50 (nM)	32	N/A	N/A	A28790
IC 50 (nM)	10	N/A	N/A	A29135
IC 50 (nM)	2	N/A	N/A	A28028
IC 50 (nM)	5.7	N/A	N/A	A29136
Ki (nM)	20.5	8	37	A29126
Ki (nM)	20.5	N/A	N/A	A29127 / A29131
Ki (nM)	2.9	8	25	A27988
Ki (nM)	26	N/A	N/A	A29134
Ki (nM)	7.2	N/A	N/A	A29137

Details1. Acetylcholinesterase

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Hydrolyzes rapidly the acetylcholine neurotransmitter released into the synaptic cleft allowing to terminate the signal transduction at the neuromuscular junction. Role in neuronal apoptosis
Specific Function: acetylcholine binding
Gene Name: ACHE
Uniprot ID: P22303
Uniprot Name: Acetylcholinesterase
Molecular Weight: 67795.525 Da

References

Davis KL: Alzheimer's disease: seeking new ways to preserve brain function. Interview by Alice V. Luddington. Geriatrics. 1999 Feb;54(2):42-7; quiz 48. [Article]
Kryger G, Silman I, Sussman JL: Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. Structure. 1999 Mar 15;7(3):297-307. [Article]
Shepherd G, Klein-Schwartz W, Edwards R: Donepezil overdose: a tenfold dosing error. Ann Pharmacother. 1999 Jul-Aug;33(7-8):812-5. [Article]
Kosasa T, Kuriya Y, Matsui K, Yamanishi Y: Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats. Eur J Pharmacol. 1999 Sep 10;380(2-3):101-7. [Article]
Jann MW: Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease. Pharmacotherapy. 2000 Jan;20(1):1-12. [Article]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Sugimoto H: Donepezil hydrochloride: a treatment drug for Alzheimer's disease. Chem Rec. 2001;1(1):63-73. [Article]
Ki YS, Park EY, Lee HW, Oh MS, Cho YW, Kwon YK, Moon JH, Lee KT: Donepezil, a potent acetylcholinesterase inhibitor, induces caspase-dependent apoptosis in human promyelocytic leukemia HL-60 cells. Biol Pharm Bull. 2010;33(6):1054-9. [Article]
Repantis D, Laisney O, Heuser I: Acetylcholinesterase inhibitors and memantine for neuroenhancement in healthy individuals: a systematic review. Pharmacol Res. 2010 Jun;61(6):473-81. doi: 10.1016/j.phrs.2010.02.009. Epub 2010 Mar 1. [Article]
FDA Approved Drug Products: Aricept/Aricept ODT (donepezil hydrochloride) tablets for oral use [Link]

Details2. 5-hydroxytryptamine receptor 2A

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inducer
Curator comments: This is a potential target of donepezil.

General Function: G-protein coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:1330647, PubMed:18703043, PubMed:19057895, PubMed:21645528, PubMed:22300836, PubMed:35084960, PubMed:38552625). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD) (PubMed:28129538, PubMed:35084960). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:28129538, PubMed:35084960). HTR2A is coupled to G(q)/G(11) G alpha proteins and activates phospholipase C-beta, releasing diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) second messengers that modulate the activity of phosphatidylinositol 3-kinase and promote the release of Ca(2+) ions from intracellular stores, respectively (PubMed:18703043, PubMed:28129538, PubMed:35084960). Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways (PubMed:28129538, PubMed:35084960). Affects neural activity, perception, cognition and mood (PubMed:18297054). Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction (By similarity)
Specific Function: 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding
Gene Name: HTR2A
Uniprot ID: P28223
Uniprot Name: 5-hydroxytryptamine receptor 2A
Molecular Weight: 52602.58 Da

References

Hayslett RL, Tizabi Y: Effects of donepezil, nicotine and haloperidol on the central serotonergic system in mice: implications for Tourette's syndrome. Pharmacol Biochem Behav. 2005 Aug;81(4):879-86. [Article]
Hayslett RL, Tizabi Y: Effects of donepezil on DOI-induced head twitch response in mice: implications for Tourette syndrome. Pharmacol Biochem Behav. 2003 Dec;76(3-4):409-15. [Article]

Details3. Cholinesterase

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inducer
Curator comments: This is a potential target, based on data from in vitro studies.

General Function: Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters
Specific Function: acetylcholinesterase activity
Gene Name: BCHE
Uniprot ID: P06276
Uniprot Name: Cholinesterase
Molecular Weight: 68417.575 Da

References

Seltzer B: Donepezil: a review. Expert Opin Drug Metab Toxicol. 2005 Oct;1(3):527-36. doi: 10.1517/17425255.1.3.527 . [Article]
Liston DR, Nielsen JA, Villalobos A, Chapin D, Jones SB, Hubbard ST, Shalaby IA, Ramirez A, Nason D, White WF: Pharmacology of selective acetylcholinesterase inhibitors: implications for use in Alzheimer's disease. Eur J Pharmacol. 2004 Feb 13;486(1):9-17. doi: 10.1016/j.ejphar.2003.11.080. [Article]
Nordberg A, Ballard C, Bullock R, Darreh-Shori T, Somogyi M: A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer's disease. Prim Care Companion CNS Disord. 2013;15(2). pii: 12r01412. doi: 10.4088/PCC.12r01412. Epub 2013 Mar 7. [Article]
Ogura H, Kosasa T, Kuriya Y, Yamanishi Y: Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro. Methods Find Exp Clin Pharmacol. 2000 Oct;22(8):609-13. [Article]

Details4. Nitric oxide synthase 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor
Inducer
Curator comments: This target action is likely mediated via donepezil's effect on microglial cells.

General Function: Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR
Specific Function: arginine binding
Gene Name: NOS1
Uniprot ID: P29475
Uniprot Name: Nitric oxide synthase 1
Molecular Weight: 160969.095 Da

References

Hwang J, Hwang H, Lee HW, Suk K: Microglia signaling as a target of donepezil. Neuropharmacology. 2010 Jun;58(7):1122-9. doi: 10.1016/j.neuropharm.2010.02.003. Epub 2010 Feb 11. [Article]
Nakahata K, Kinoshita H, Hama-Tomioka K, Ishida Y, Matsuda N, Hatakeyama N, Haba M, Kondo T, Hatano Y: Cholinesterase inhibitor donepezil dilates cerebral parenchymal arterioles via the activation of neuronal nitric oxide synthase. Anesthesiology. 2008 Jul;109(1):124-9. doi: 10.1097/ALN.0b013e31817c0316. [Article]
Haraguchi Y, Mizoguchi Y, Ohgidani M, Imamura Y, Murakawa-Hirachi T, Nabeta H, Tateishi H, Kato TA, Monji A: Donepezil suppresses intracellular Ca(2+) mobilization through the PI3K pathway in rodent microglia. J Neuroinflammation. 2017 Dec 22;14(1):258. doi: 10.1186/s12974-017-1033-0. [Article]

Details5. Tumor necrosis factor-inducible gene 6 protein

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Major regulator of extracellular matrix organization during tissue remodeling (PubMed:15917224, PubMed:18042364, PubMed:26823460). Catalyzes the transfer of a heavy chain (HC) from inter-alpha-inhibitor (I-alpha-I) complex to hyaluronan. Cleaves the ester bond between the C-terminus of the HC and GalNAc residue of the chondroitin sulfate chain in I-alpha-I complex followed by transesterification of the HC to hyaluronan. In the process, potentiates the antiprotease function of I-alpha-I complex through release of free bikunin (PubMed:15917224, PubMed:16873769, PubMed:20463016). Acts as a catalyst in the formation of hyaluronan-HC oligomers and hyaluronan-rich matrix surrounding the cumulus cell-oocyte complex, a necessary step for oocyte fertilization (PubMed:26468290). Assembles hyaluronan in pericellular matrices that serve as platforms for receptor clustering and signaling. Enables binding of hyaluronan deposited on the surface of macrophages to LYVE1 on lymphatic endothelium and facilitates macrophage extravasation. Alters hyaluronan binding to functionally latent CD44 on vascular endothelium, switching CD44 into an active state that supports leukocyte rolling (PubMed:15060082, PubMed:26823460). Modulates the interaction of chemokines with extracellular matrix components and proteoglycans on endothelial cell surface, likely preventing chemokine gradient formation (PubMed:27044744). In a negative feedback mechanism, may limit excessive neutrophil recruitment at inflammatory sites by antagonizing the association of CXCL8 with glycosaminoglycans on vascular endothelium (PubMed:24501198). Has a role in osteogenesis and bone remodeling. Inhibits BMP2-dependent differentiation of mesenchymal stem cell to osteoblasts (PubMed:16771708, PubMed:18586671). Protects against bone erosion during inflammation by inhibiting TNFSF11/RANKL-dependent osteoclast activation (PubMed:18586671)
Specific Function: calcium ion binding
Gene Name: TNFAIP6
Uniprot ID: P98066
Uniprot Name: Tumor necrosis factor-inducible gene 6 protein
Molecular Weight: 31203.09 Da

References

Hwang J, Hwang H, Lee HW, Suk K: Microglia signaling as a target of donepezil. Neuropharmacology. 2010 Jun;58(7):1122-9. doi: 10.1016/j.neuropharm.2010.02.003. Epub 2010 Feb 11. [Article]

Details6. Interleukin-1 beta

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor
Inducer

General Function: Potent pro-inflammatory cytokine (PubMed:10653850, PubMed:12794819, PubMed:28331908, PubMed:3920526). Initially discovered as the major endogenous pyrogen, induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, B-cell activation and antibody production, and fibroblast proliferation and collagen production (PubMed:3920526). Promotes Th17 differentiation of T-cells. Synergizes with IL12/interleukin-12 to induce IFNG synthesis from T-helper 1 (Th1) cells (PubMed:10653850). Plays a role in angiogenesis by inducing VEGF production synergistically with TNF and IL6 (PubMed:12794819). Involved in transduction of inflammation downstream of pyroptosis: its mature form is specifically released in the extracellular milieu by passing through the gasdermin-D (GSDMD) pore (PubMed:33377178, PubMed:33883744). Acts as a sensor of S.pyogenes infection in skin: cleaved and activated by pyogenes SpeB protease, leading to an inflammatory response that prevents bacterial growth during invasive skin infection (PubMed:28331908)
Specific Function: cytokine activity
Gene Name: IL1B
Uniprot ID: P01584
Uniprot Name: Interleukin-1 beta
Molecular Weight: 30747.7 Da

References

Hwang J, Hwang H, Lee HW, Suk K: Microglia signaling as a target of donepezil. Neuropharmacology. 2010 Jun;58(7):1122-9. doi: 10.1016/j.neuropharm.2010.02.003. Epub 2010 Feb 11. [Article]
Reale M, Iarlori C, Gambi F, Lucci I, Salvatore M, Gambi D: Acetylcholinesterase inhibitors effects on oncostatin-M, interleukin-1 beta and interleukin-6 release from lymphocytes of Alzheimer's disease patients. Exp Gerontol. 2005 Mar;40(3):165-71. doi: 10.1016/j.exger.2004.12.003. Epub 2005 Jan 8. [Article]
Zhang T, Tian F, Wang J, Zhou S, Dong X, Guo K, Jing J, Zhou Y, Chen Y: Donepezil attenuates high glucose-accelerated senescence in human umbilical vein endothelial cells through SIRT1 activation. Cell Stress Chaperones. 2015 Sep;20(5):787-92. doi: 10.1007/s12192-015-0601-4. Epub 2015 Jul 21. [Article]

Details7. Nuclear factor NF-kappa-B (Protein Group)

Kind: Protein group
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. In a non-canonical activation pathway, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. The NF-kappa-B heterodimeric RelB-p52 complex is a transcriptional activator. The NF-kappa-B p52-p52 homodimer is a transcriptional repressor. NFKB2 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p100 and generation of p52 by a cotranslational processing. The proteasome-mediated process ensures the production of both p52 and p100 and preserves their independent function. p52 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. p52 and p100 are respectively the minor and major form; the processing of p100 being relatively poor. Isoform p49 is a subunit of the NF-kappa-B protein complex, which stimulates the HIV enhancer in synergy with p65. In concert with RELB, regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer
Specific Function: DNA-binding transcription activator activity, RNA polymerase II-specific

Components:

Name	UniProt ID
Nuclear factor NF-kappa-B p100 subunit	Q00653
Nuclear factor NF-kappa-B p105 subunit	P19838

References

Kim HG, Moon M, Choi JG, Park G, Kim AJ, Hur J, Lee KT, Oh MS: Donepezil inhibits the amyloid-beta oligomer-induced microglial activation in vitro and in vivo. Neurotoxicology. 2014 Jan;40:23-32. doi: 10.1016/j.neuro.2013.10.004. Epub 2013 Nov 1. [Article]
Srinivasan M, Lahiri DK: Significance of NF-kappaB as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer's disease and multiple sclerosis. Expert Opin Ther Targets. 2015 Apr;19(4):471-87. doi: 10.1517/14728222.2014.989834. Epub 2015 Feb 4. [Article]

Details8. NMDA receptor (Protein Group)

Kind: Protein group
Organism: Humans
Pharmacological action: Unknown
Actions: Downregulator

General Function: Component of NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:26875626, PubMed:26919761, PubMed:28105280, PubMed:28126851, PubMed:7685113). Sensitivity to glutamate and channel kinetics depend on the subunit composition (PubMed:26919761)
Specific Function: amyloid-beta binding

Components:

Name	UniProt ID
Glutamate receptor ionotropic, NMDA 1	Q05586
Glutamate receptor ionotropic, NMDA 2A	Q12879
Glutamate receptor ionotropic, NMDA 2B	Q13224
Glutamate receptor ionotropic, NMDA 2C	Q14957
Glutamate receptor ionotropic, NMDA 2D	O15399
Glutamate receptor ionotropic, NMDA 3A	Q8TCU5
Glutamate receptor ionotropic, NMDA 3B	O60391

References

Shen H, Kihara T, Hongo H, Wu X, Kem WR, Shimohama S, Akaike A, Niidome T, Sugimoto H: Neuroprotection by donepezil against glutamate excitotoxicity involves stimulation of alpha7 nicotinic receptors and internalization of NMDA receptors. Br J Pharmacol. 2010 Sep;161(1):127-39. doi: 10.1111/j.1476-5381.2010.00894.x. [Article]

Enzymes

Details1. Cytochrome P450 2D6

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
Specific Function: anandamide 11,12 epoxidase activity
Gene Name: CYP2D6
Uniprot ID: P10635
Uniprot Name: Cytochrome P450 2D6
Molecular Weight: 55768.94 Da

References

Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
Coin A, Pamio MV, Alexopoulos C, Granziera S, Groppa F, de Rosa G, Girardi A, Sergi G, Manzato E, Padrini R: Donepezil plasma concentrations, CYP2D6 and CYP3A4 phenotypes, and cognitive outcome in Alzheimer's disease. Eur J Clin Pharmacol. 2016 Jun;72(6):711-7. doi: 10.1007/s00228-016-2033-1. Epub 2016 Mar 8. [Article]
Anil Kumar; Sandeep Sharma (2019). Donepezil. Stat Pearls.
Flockhart Table of Drug Interactions [Link]

Details2. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function: 1,8-cineole 2-exo-monooxygenase activity
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
Coin A, Pamio MV, Alexopoulos C, Granziera S, Groppa F, de Rosa G, Girardi A, Sergi G, Manzato E, Padrini R: Donepezil plasma concentrations, CYP2D6 and CYP3A4 phenotypes, and cognitive outcome in Alzheimer's disease. Eur J Clin Pharmacol. 2016 Jun;72(6):711-7. doi: 10.1007/s00228-016-2033-1. Epub 2016 Mar 8. [Article]
Anil Kumar; Sandeep Sharma (2019). Donepezil. Stat Pearls.

Details3. Cytochrome P450 2C9

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
Specific Function: (R)-limonene 6-monooxygenase activity
Gene Name: CYP2C9
Uniprot ID: P11712
Uniprot Name: Cytochrome P450 2C9
Molecular Weight: 55627.365 Da

References

Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
Lu J, Wan L, Zhong Y, Yu Q, Han Y, Chen P, Wang B, Li W, Miao Y, Guo C: Stereoselective metabolism of donepezil and steady-state plasma concentrations of S-donepezil based on CYP2D6 polymorphisms in the therapeutic responses of Han Chinese patients with Alzheimer's disease. J Pharmacol Sci. 2015 Nov;129(3):188-95. doi: 10.1016/j.jphs.2015.10.010. Epub 2015 Nov 5. [Article]

Transporters

Details1. Broad substrate specificity ATP-binding cassette transporter ABCG2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
Specific Function: ABC-type xenobiotic transporter activity
Gene Name: ABCG2
Uniprot ID: Q9UNQ0
Uniprot Name: Broad substrate specificity ATP-binding cassette transporter ABCG2
Molecular Weight: 72313.47 Da

References

Takeuchi R, Shinozaki K, Nakanishi T, Tamai I: Local Drug-Drug Interaction of Donepezil with Cilostazol at Breast Cancer Resistance Protein (ABCG2) Increases Drug Accumulation in Heart. Drug Metab Dispos. 2016 Jan;44(1):68-74. doi: 10.1124/dmd.115.066654. Epub 2015 Oct 14. [Article]

Drug created at June 13, 2005 13:24 / Updated at October 10, 2024 16:42

Donepezil

Identification

Structure for Donepezil (DB00843)

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Clinical Trial & Rare Diseases Add-on Data Package

Pharmacoeconomics

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