Rivastigmine: Difference between revisions
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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> | ! 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><ref>PMID: 12431053</ref> | ||
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! Parameter | ! Parameter | ||
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! 6.7 <br/>(Rat) | ! 6.7 <br/>(Rat) | ||
! 450 <br/>(Human) | ! 450 <br/>(Human) | ||
! | ! 920 <br/>(Human) | ||
! 1995 <br/>(Rat) | ! 1995 <br/>(Rat) | ||
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Revision as of 14:52, 1 December 2010
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Better Known as: Exelon
- Marketed By:
- Major Indication: Alzheimer's Disease
- Drug Class: Acetylcholinesterase Inhibitor
- Date of FDA Approval (Patent Expiration):
- 2006 Sales: $220 Million[1]
- Why You Should Care: One of the the first 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
Mechanism of Action
is a carbamate inhibitor of AChE, and it is currenly used in therapy of Alzheimer's disease. Rivastigmine (colored yellow) interacts with TcAChE (colored lime) at the (1gqr). The carbamyl moiety of rivastigmine is to the active-site S200 Oγ. The second part of rivastigmine (the leaving group), NAP ((−)-S-3-[1-(dimethylamino)ethyl]phenol) is also held in the active-site gorge, but it is from the carbamyl moiety, hence, carbamylation took place. The of TcAChE/NAP (colored magenta) is known (1gqs). The TcAChE active-site residues which are interacting with NAP are colored violet. NAP is located in a similar region of TcAChE active site, but with different orientation than that of the NAP part (colored yellow) in the TcAChE/rivastigmine complex. Only H440 and F330 significantly change their side-chain conformations. of the TcAChE active sites in 4 different structures (TcAChE/rivastigmine (1gqr), TcAChE/NAP (1gqs), native TcAChE (2ace), and TcAChE/VX (1vxr, TcAChE colored white and VX black) reveals that the conformation of H440 in the TcAChE/NAP structure is very similar its conformation in the native TcAChE (2ace), but the distance between H440 Nδ and E327 Oε is significantly longer in the TcAChE/rivastigmine and the TcAChE/VX complexes. This structural change disrupts the catalytic triad consisting of S200, E327, H440. This could explain the very slow kinetics of AChE reactivation after its inhibition by rivastigmine [2].
Pharmacokinetics
| Aceylcholinesterase Inhibitor Pharmacokinetics[3][4][5][6][7][8][9][10] | ||||||
|---|---|---|---|---|---|---|
| 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) |
920 (Human) |
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)
- ↑ Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman JL, Silman I. Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine. Biochemistry. 2002 Mar 19;41(11):3555-64. PMID:11888271
- ↑ 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
- ↑ Sterling J, Herzig Y, Goren T, Finkelstein N, Lerner D, Goldenberg W, Miskolczi I, Molnar S, Rantal F, Tamas T, Toth G, Zagyva A, Zekany A, Finberg J, Lavian G, Gross A, Friedman R, Razin M, Huang W, Krais B, Chorev M, Youdim MB, Weinstock M. Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease. J Med Chem. 2002 Nov 21;45(24):5260-79. PMID:12431053