Donepezil
|
Better Known as: Aricept
- Marketed By: Eisai & Pfizer
- Major Indication: Alzheimer's Disease
- Drug Class: Acetylcholinesterase Inhibitor
- Date of FDA Approval (Patent Expiration): 1996 (2008)
- 2006 Sales: $1.4 Billion[1]
- Why You Should Care: One of the most effective treatments for the symptoms of Alzheimer's Disease, although no definitive proof exists as to whether to alters the progression of the disease.
- The following is a list of Pharmacokinetic Parameters. See: Pharmaceutical Drugs for more information
Mechanism of Action
Donepezil is a potent Acetylcholinesterase (AChE) inhibitor to the active site of . By inhibiting AChE, the important neurotransmitter, acetylcholine, is degraded at a slower rate, helping reverse the marked decrease in neuronal function evident in Alzheimer's Disease patients. Donepezil binds along the active-site gorge, extending from the anionic subsite to the peripheral anionic site . Interestingly, it does not directly interact with the catalytic triad of acetylcholinesterase nor the oxyanion hole. Further, donepezil does not form any direct hydrogen bonds with AChE nor electrostatic interactions, but rather only interacts via aromatic stacking and solvent mediated interactions. It with Glu 199, His 440, Phe 330, Trp 84, Tyr 334, Tyr 121, Phe 331, Phe 288, Ser 286, Phe 290, Arg 289, Trp 279, & Leu 282 to tightly bind to AChE. [2]
Pharmacokinetics
| Aceylcholinesterase Inhibitor Pharmacokinetics[3][4][5][6][7][8][9] | ||||||
|---|---|---|---|---|---|---|
| Parameter | Donepezil | Tacrine | Rivastigmine | Galantamine | ||
| Tmax (hr) | 3.6 | 1.5 | .3 | 1.2 | ||
| Cmax (ng/ml) | 6.5 | 15.7 | 29.3 | 42.6 | ||
| Bioavailability (%) | 100 | 17 | 36 | 100 | ||
| Protein Binding (%) | 96 | 55 | 40 | 10 | ||
| T1/2 (hr) | 70 | 3 | 5 | 7.3 | ||
| AUC (ng/ml/hr) | 380 | 80.4 | 191 | 427 | ||
| IC50 (nM) | 6.7 (Rat) |
450 (Human) |
181390 (Rat) |
1995 (Rat) | ||
| Dosage (mg) | 5 | 160 | 6 | 8 | ||
| Metabolism | Hepatic (CYP2D6 & CYP3A4) & Cholinesterase | Hepatic (CYP1A2) & Cholinesterase | Cholinesterase | Hepatic (CYP3A4 & CYP2D6) & Cholinesterase | ||
References
- ↑ Irena Melnikova, Therapies for Alzheimer's disease, Nature Reviews Drug Discovery 6, 341-342 (May 2007)
- ↑ 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. PMID:10368299
- ↑ Apostolou C, Dotsikas Y, Kousoulos C, Loukas YL. Quantitative determination of donepezil in human plasma by liquid chromatography/tandem mass spectrometry employing an automated liquid-liquid extraction based on 96-well format plates. Application to a bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Apr 1;848(2):239-44., Epub 2006 Nov 17. PMID:17113365 doi:10.1016/j.jchromb.2006.10.037
- ↑ Ota T, Shinotoh H, Fukushi K, Kikuchi T, Sato K, Tanaka N, Shimada H, Hirano S, Miyoshi M, Arai H, Suhara T, Irie T. Estimation of plasma IC50 of donepezil for cerebral acetylcholinesterase inhibition in patients with Alzheimer disease using positron emission tomography. Clin Neuropharmacol. 2010 Mar-Apr;33(2):74-8. PMID:19935404 doi:10.1097/WNF.0b013e3181c71be9
- ↑ Mori F, Lai CC, Fusi F, Giacobini E. Cholinesterase inhibitors increase secretion of APPs in rat brain cortex. Neuroreport. 1995 Mar 7;6(4):633-6. PMID:7605915
- ↑ Farlow M, Gracon SI, Hershey LA, Lewis KW, Sadowsky CH, Dolan-Ureno J. A controlled trial of tacrine in Alzheimer's disease. The Tacrine Study Group. JAMA. 1992 Nov 11;268(18):2523-9. PMID:1404819
- ↑ Laine K, Palovaara S, Tapanainen P, Manninen P. Plasma tacrine concentrations are significantly increased by concomitant hormone replacement therapy. Clin Pharmacol Ther. 1999 Dec;66(6):602-8. PMID:10613616 doi:10.1053/cp.1999.v66.103404001
- ↑ Lefevre G, Sedek G, Jhee SS, Leibowitz MT, Huang HL, Enz A, Maton S, Ereshefsky L, Pommier F, Schmidli H, Appel-Dingemanse S. Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer's disease patients. Clin Pharmacol Ther. 2008 Jan;83(1):106-14. Epub 2007 May 23. PMID:17522596 doi:10.1038/sj.clpt.6100242
- ↑ Takada Y, Yonezawa A, Kume T, Katsuki H, Kaneko S, Sugimoto H, Akaike A. Nicotinic acetylcholine receptor-mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons. J Pharmacol Exp Ther. 2003 Aug;306(2):772-7. Epub 2003 May 6. PMID:12734391 doi:10.1124/jpet.103.050104