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| <applet load="" size="480" color="" frame="true" spin="on" Scene ="Cerivastatin/Ceriv/1" align="right" caption="Donepezil, also known as Aricept"/> | | <applet load="" size="480" color="" frame="true" spin="on" Scene ="Donepezil/Donepezil/1" align="right" caption="Donepezil, also known as Aricept"/> |
| ===Better Known as: Aricept=== | | ===Better Known as: Aricept=== |
| * Marketed By: Eisai & Pfizer <br /> | | * Marketed By: Eisai & Pfizer <br /> |
| * Major Indication: Alzheimer's Disease<br /> | | * Major Indication: [[Alzheimer's Disease]]<br /> |
| * Drug Class: [[Acetylcholinesterase]] Inhibitor | | * Drug Class: [[Acetylcholinesterase]] Inhibitor |
| * Date of FDA Approval (Withdrawn): 1996 (2008)<br /> | | * Date of FDA Approval (Patent Expiration): 1996 (2008)<br /> |
| * 2006 Sales: $800 Million | | * 2006 Sales: $1.4 Billion<ref>Irena Melnikova, Therapies for Alzheimer's disease, Nature Reviews Drug Discovery 6, 341-342 (May 2007)</ref> |
| * 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. | | * Importance: One of the most effective treatments for the symptoms of [[Alzheimer's Disease]], although no definitive proof exists as to whether it alters the progression of the disease. |
| * The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information | | * See: [[Pharmaceutical Drugs]] for more information about other drugs and disorders |
| | |
| ===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>. | | Donepezil is a potent [[Acetylcholinesterase]] (AChE) inhibitor to the active site of <scene name='Donepezil/Ache/1'>AChE</scene>. 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 <scene name='Donepezil/Trp_84/1'>near Trp 84</scene> to the peripheral anionic site <scene name='Donepezil/Trp_279/1'>near Trp 279</scene>. 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 <scene name='Donepezil/Bound/1'>primarily interacts</scene> 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.<ref name="Kryger">PMID:10368299</ref> |
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| ===Pharmacokinetics=== | | ===Pharmacokinetics=== |
| {| class="wikitable" border="1" width="48%" style="text-align:center"
| | <table style="background: cellspacing="0px" align="" cellpadding="0px" width="42%"> |
| |-
| | <tr> |
| ! colspan="7" align="center"| Aceylcholinesterase Inhibitor [[Pharmaceutical_Drugs#Pharmacokinetics_Translated|Pharmacokinetics]]<ref>PMID:17113365</ref><ref>PMID: 19935404</ref><ref>PMID:7605915</ref><ref>PMID:1404819</ref><ref>doi:10.1053/cp.1999.v66.103404001</ref><ref>doi:10.1038/sj.clpt.6100242</ref><ref>PMID:12734391</ref>
| | <td style="width:100%; vertical-align:top;border-width:0px; border-style:inset"> |
| |-
| | <div style="height:100%; width: 100%"> |
| ! Parameter
| | {{:Acetylcholinesterase Inhibitor Pharmacokinetics}} |
| ! [[Donepezil]]
| | </div> |
| ! [[Tacrine]]
| | </td> |
| ! [[Rivastigmine]]
| | </tr> |
| ! [[Galantamine]]
| | </table> |
| |-
| |
| ! [[Pharmaceutical_Drugs#Tmax|T<sub>max</sub>]] (hr)
| |
| ! 3.6
| |
| ! 1.5
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| ! .3
| |
| ! 1.2
| |
| |-
| |
| ! [[Pharmaceutical_Drugs#Cmax|C<sub>max</sub>]] (ng/ml)
| |
| ! 6.5
| |
| ! 15.7
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| ! 29.3
| |
| ! 42.6
| |
| |-
| |
| ! [[Pharmaceutical_Drugs#Bioavailability_.28F.29|Bioavailability]] (%)
| |
| ! 100
| |
| ! 17
| |
| ! 36
| |
| ! 100
| |
| |-
| |
| ! [[Pharmaceutical_Drugs#Protein_Binding|Protein Binding]] (%)
| |
| ! 96
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| ! 55
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| ! 40
| |
| ! 10
| |
| |-
| |
| ! [[Pharmaceutical_Drugs#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
| |
| ! 70
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| ! 3
| |
| ! 5
| |
| ! 7.3
| |
| |-
| |
| ! [[Pharmaceutical_Drugs#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
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| ! 380
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| ! 80.4
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| ! 191
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| ! 427
| |
| |-
| |
| ! [[Pharmaceutical_Drugs#Inhibitory_Concentration_.28IC50.29|IC<sub>50</sub>]] (nM)
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| ! 6.7 <br/>(Rat)
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| ! 450 <br/>(Human)
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| ! 181390 <br/>(Rat)
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| ! 1995 <br/>(Rat)
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| |-
| |
| ! Dosage (mg)
| |
| ! 5
| |
| ! 160
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| ! 6
| |
| ! 8
| |
| |-
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| ! Metabolism
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| ! Hepatic (CYP2D6 & CYP3A4)
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| ! Hepatic (CYP1A2)
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| ! Cholinesterase
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| ! Hepatic (CYP3A4 & CYP2D6) & Cholinesterase
| |
| |}
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| ===References=== | | ===References=== |