Rivastigmine
|
Better Known as: Exelon
- Marketed By: Novartis
- Major Indication: Alzheimer's Disease
- Drug Class: Acetylcholinesterase Inhibitor
- Date of FDA Approval (Patent Expiration): 2007 (
- 2006 Sales: $220 Million[1]
- Importance: 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.
- See: Pharmaceutical Drugs for more information about other drugs and disorders
Mechanism of Action
Rivastigmine is an Acetylcholinesterase (AChE) inhibitor. It binds to the active site of , utilizing many of the same residues which bind and break down acetylcholine. 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. Rivastigmine is rapidly metabolized into its principal components (carbamyl and NAP moieties) which are powerful Acetylcholine inhibitors. These components primarily GLy 117, Gly 118, Gly 119 Ala 201, Trp 233, Phe 290, Trp 84, Phe 330, His 440, & Phe 288 in tightly binding to the AChE binding site via pi stacking and hydrogen bond interactions. Rivastigmine outcompetes acetylcholine for the active site of AChE, inhibiting the esterase.[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) |
1535 (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
- ↑ Camps P, Gomez E, Munoz-Torrero D, Badia A, Vivas NM, Barril X, Orozco M, Luque FJ. Synthesis, in vitro pharmacology, and molecular modeling of syn-huprines as acetylcholinesterase inhibitors. J Med Chem. 2001 Dec 20;44(26):4733-6. PMID:11741490