Donepezil: Difference between revisions

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* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information
* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information
===Mechanism of Action===
===Mechanism of Action===
<scene name='Main_Page/E2020_in_ache_spinning/1'>Aricept (E2020)</scene> is one of the most interesting drugs that have been designed as AChE bivalent inhibitors. It was developed, synthesized and evaluated by the Eisai Company in Japan. These inhibitors were designed on the basis of QSAR studies prior to elucidation of the 3D structure of ''Torpedo californica'' AChE (''Tc''AChE) ([[1ea5]]). It significantly enhances performance in animal models of cholinergic hypofunction and has a high affinity for AChE, binding to both electric eel and mouse AChE in the nanomolar range. The X-ray structure of the E2020-''Tc''AChE complex ([[1eve]]) shows that E2020 has a <scene name='1eve/E2020_close_up_with_84_279/13'>unique orientation</scene> along the active-site gorge, extending from the anionic subsite (<scene name='1eve/E2020_close_up_with_84lbld/7'>W84</scene>) of the active site, at the bottom, to the peripheral anionic site (<scene name='1eve/E2020_close_up_with_84_279lbld/5'>near W279</scene>), at the top, via aromatic stacking interactions with conserved aromatic acid residues. E2020 does not, however, interact directly with either the catalytic triad or the 'oxyanion hole' but only <scene name='1eve/E20_interactionshown/8'>indirectly via solvent molecules</scene>. The X-ray structure shows, a posteriori, that the design of E2020 took advantage of several important features of the active-site gorge of AChE, to produce a drug with both high affinity for AChE and a high degree of selectivity for AChE versus butyrylcholinesterase (BChE). It also delineates voids within the gorge that are not occupied by E2020 and could provide sites for potential modification of E2020 to produce drugs with improved pharmacological profiles <ref name="Kryger">PMID:10368299</ref>.
Aricept is a potent [[Acetylcholinesterase]] inhibitor. It binds along the active-site gorge, extending from the anionic subsite (W84) to the peripheral anionic site (w279). Interestingly, it does not directly interact with the catalytic triad or Oxyanion hole of AChE, but rather only interacts via aromatic stacking and solvent mediated interactions.  


<scene name='Donepezil/Ache/1'>TextToBeDisplayed</scene>
<scene name='Donepezil/Bound/1'>TextToBeDisplayed</scene>
===Pharmacokinetics===
===Pharmacokinetics===
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Revision as of 15:22, 30 November 2010

Donepezil, also known as Aricept

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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: $800 Million
  • Why You Should Care: One of the most effective treatments for teh 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

Aricept is a potent Acetylcholinesterase inhibitor. It binds along the active-site gorge, extending from the anionic subsite (W84) to the peripheral anionic site (w279). Interestingly, it does not directly interact with the catalytic triad or Oxyanion hole of AChE, but rather only interacts via aromatic stacking and solvent mediated interactions.


Pharmacokinetics

Aceylcholinesterase Inhibitor Pharmacokinetics[1][2][3][4][5][6][7]
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) Hepatic (CYP1A2) Cholinesterase Hepatic (CYP3A4 & CYP2D6) & Cholinesterase

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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


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