Galantamine
|
Better Known as: Razadyne
- Marketed By: Ortho Mcneil Janssen Pharmaceuticals (Subsidiary of Johnson & Johnson)
- Major Indication: Alzheimer's Disease
- Drug Class: Acetylcholinesterase Inhibitor
- Date of FDA Approval (Patent Expiration): 2001 (2008)
- 2006 Sales: $225 Million[1]
- Importance: Part of a newer generation of treatments for 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
Described above, (abbreviated as ; colored red) is a CAS-binding inhibitor and it is currently used in therapy of the AD. Conjugate of GAL through the (8 carbons, yellow) with a (blueviolet) called compound 3 has a larger affinity for AChE than that of GAL alone. This is similar to previously described cases of bivalent ligands (e.g. (RS)-(±)-tacrine-(10)-hupyridone). A comparison between /TcAChE (1w4l) and structure (1dx6) shows an identical binding mode of the GAL-moiety (transparent red) of compound 3 to that of GAL alone (blue) at the CAS. A PEG molecule (gray) is located at the active site of the galanthamine/TcAChE structure. The alkyl linker spans the active-site gorge and the phthalimido moiety of compound 3 is situated near Trp279 at the PAS. Compound 3 has higher affinity to TcAChE than GAL. This can be explained by the higher number of interactions between compound 3 (which interacts not only with residues within CAS but also within PAS) and TcAChE relative to GAL [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)
- ↑ Greenblatt HM, Guillou C, Guenard D, Argaman A, Botti S, Badet B, Thal C, Silman I, Sussman JL. The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design. J Am Chem Soc. 2004 Dec 1;126(47):15405-11. PMID:15563167 doi:http://dx.doi.org/10.1021/ja0466154
- ↑ 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