Tacrine

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Tacrine, also known as Cognex

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Better Known as: Cognex

  • Marketed By: Parke Davis Pharmaceuticals
  • Major Indication: Alzheimer's Disease
  • Drug Class: Acetylcholinesterase Inhibitor
  • Date of FDA Approval (Patent Expiration): 1993 (N/A)
  • 1994 Sales: $100 Million
  • 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

Tacrine is an Acetylcholinesterase (AChE) inhibitor. It binds to the active site of , utilizing many of the same residues which . 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. Tacrine Phe 330, His 440, Trp 84, & Ser 200 in tightly binding to the AChE binding site via pi stacking interactions. It is clearly visible how with the binding of acetylcholine, outcompeting acetylcholine for nearly the same space in the active site. [1]

Pharmacokinetics

Aceylcholinesterase Inhibitor Pharmacokinetics[2][3][4][5][6][7][8]
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) 		181390
(Rat) 		1995
(Rat)
Dosage (mg) 5 160 6 8
Metabolism Hepatic (CYP2D6 & CYP3A4) & Cholinesterase Hepatic (CYP1A2) & Cholinesterase Cholinesterase Hepatic (CYP3A4 & CYP2D6) & Cholinesterase

References

  1. ↑ Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, Axelsen PH, Silman I, Sussman JL. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9031-5. PMID:8415649
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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


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