Donepezil

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<applet load="" size="480" color="" frame="true" spin="on" Scene ="Donepezil/Donepezil/1" align="right" caption="Donepezil, also known as Aricept"/>
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==Donepezil==
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<StructureSection load='' size='490' side='right' caption='Donepezil, also known as Aricept' scene='42/428165/Donepezil/2'>
===Better Known as: Aricept===
===Better Known as: Aricept===
* Marketed By: Eisai & Pfizer <br />
* Marketed By: Eisai & Pfizer <br />
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* Drug Class: [[Acetylcholinesterase]] Inhibitor
* Drug Class: [[Acetylcholinesterase]] Inhibitor
* Date of FDA Approval (Patent Expiration): 1996 (2008)<br />
* Date of FDA Approval (Patent Expiration): 1996 (2008)<br />
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* 2006 Sales: $800 Million
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* 2006 Sales: $1.4 Billion<ref>Irena Melnikova, Therapies for Alzheimer's disease, Nature Reviews Drug Discovery 6, 341-342 (May 2007)</ref>
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* 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.
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* 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.
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* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information
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* See: [[Pharmaceutical Drugs]] for more information about other drugs and disorders
===Mechanism of Action===
===Mechanism of Action===
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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 near <scene name='Donepezil/Trp_84/1'>Trp 84</scene> to the peripheral anionic site near <scene name='Donepezil/Trp_279/1'>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.
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Donepezil is a potent [[Acetylcholinesterase]] (AChE) inhibitor to the active site of <scene name='42/428165/Ache/6'>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='42/428165/Trp_84/3'>near Trp 84</scene> to the peripheral anionic site <scene name='42/428165/Trp_279/2'>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='42/428165/Bound/3'>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>. More details can be seen at [[Aricept_Complexed_with_Acetylcholinesterase]].
===Pharmacokinetics===
===Pharmacokinetics===
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{| class="wikitable" border="1" width="55%" style="text-align:center"
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<table style="background: cellspacing="0px" align="" cellpadding="0px" width="42%">
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|-
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<tr>
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! 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>
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<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">
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|-
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<div style="height:100%; width: 100%">
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! Parameter
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{{:Acetylcholinesterase Inhibitor Pharmacokinetics}}
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! [[Donepezil]]
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</div>
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! [[Tacrine]]
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</td>
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! [[Rivastigmine]]
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</tr>
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! [[Galantamine]]
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</table>
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|-
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! [[Pharmaceutical_Drugs#Tmax|T<sub>max</sub>]] (hr)
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! 3.6
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! 1.5
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! .3
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! 1.2
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|-
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! [[Pharmaceutical_Drugs#Cmax|C<sub>max</sub>]] (ng/ml)
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! 6.5
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! 15.7
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! 29.3
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! 42.6
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|-
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! [[Pharmaceutical_Drugs#Bioavailability_.28F.29|Bioavailability]] (%)
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! 100
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! 17
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! 36
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! 100
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|-
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! [[Pharmaceutical_Drugs#Protein_Binding|Protein Binding]] (%)
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! 96
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! 55
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! 40
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! 10
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|-
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! [[Pharmaceutical_Drugs#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
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! 70
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! 3
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! 5
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! 7.3
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|-
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! [[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
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! [[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)
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! 5
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! 160
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! 6
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! 8
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|-
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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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|}
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===References===
===References===
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__NOTOC__
__NOTOC__
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</StructureSection>

Current revision

Donepezil

Donepezil, also known as Aricept

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Proteopedia Page Contributors and Editors (what is this?)

David Canner, Joel L. Sussman

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