Absorption, Distribution and Excretion
Tacrine is rapidly absorbed. Absolute bioavailability of tacrine is approximately 17%.
349 ± 193 L

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Metabolism / Metabolites
Hepatic. Cytochrome P450 1A2 is the principal isozyme involved in tacrine metabolism. The major metabolite, 1-hydroxy-tacrine (velnacrine), has central cholinergic activity.
Tacrine has known human metabolites that include 4- Hydroxytacrine, N4-hydroxylamine, 2-Hydroxytacrine, and 7-Hydroxytacrine.
Hepatic. Cytochrome P450 1A2 is the principal isozyme involved in tacrine metabolism. The major metabolite, 1-hydroxy-tacrine (velnacrine), has central cholinergic activity.
Half Life: 2 to 4 hours

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Biological Half-Life
2 to 4 hours

Toxicity Summary
Tacrine is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.

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Hepatotoxicity
Strikingly, therapy with tacrine was associated with serum aminotransferase elevations in almost half of patients. These elevations usually arose within 6 to 8 weeks of starting therapy and rapidly resolved when therapy was stopped. Elevations above 3 times the upper limit of the normal range (ULN) occurred in 25%, above 10 times ULN in 6% and above 20 times ULN in 2% of patients. Accompanying elevations in alkaline phosphatase and bilirubin were rare, and the ALT abnormalities were usually asymptomatic and resolved rapidly when therapy was stopped or with dose reduction. Monitoring of serum aminotransferase levels during tacrine therapy was recommended, with dose modification for ALT elevations above 3 times the ULN and discontinuation if levels rose above 5 times the ULN. In prelicensure studies, no instances of clinically apparent acute liver injury with jaundice were reported. Subsequently, however, several cases of acute hepatocellular injury with jaundice attributed to tacrine were reported, generally arising within 2 to 8 weeks of starting therapy and usually resolving rapidly with discontinuation. Eosinophilia often accompanied the hepatic injury due to tacrine, but rash and fever were uncommon as were autoantibodies. Rechallenge often led to recurrence of the hepatic injury with a somewhat shorter latency but similar or milder course. In many patients, the serum aminotransferase elevations resolved even without drug discontinuation or dose modification. Nevertheless, fatal cases of liver injury attributed to tacrine were reported to the sponsor. Routine monitoring of serum aminotransferase levels for the first six months of therapy was recommended. However, the availability of other oral anticholinesterase inhibitors that are given only once or twice daily, do not require ALT monitoring and only rarely cause liver enzyme elevations has led to the withdrawal of tacrine from clinical use in the United States.
Likelihood score: A (well established cause of liver injury, although usually marked by serum aminotransferase elevations without symptoms or jaundice).

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Protein Binding
55%

[1]. Possible role of hydroxylated metabolites of tacrine in drug toxicity and therapy of Alzheimer's disease. Curr Drug Metab. 2008;9(4):332-335.

[2]. Assessment of the CYP1A2 Inhibition-Mediated Drug Interaction Potential for Pinocembrin Using In Silico, In Vitro, and In Vivo Approaches. ACS Omega. 2022;7(23):20321-20331. Published 2022 Jun 2.

[3]. Novel tacrine-related drugs as potential candidates for the treatment of Alzheimer's disease. Bioorg Med Chem Lett. 2013;23(7):1916-1922.

Tacrine is a member of the class of acridines that is 1,2,3,4-tetrahydroacridine substituted by an amino group at position 9. It is used in the treatment of Alzheimer's disease. It has a role as an EC 3.1.1.7 (acetylcholinesterase) inhibitor. It is a member of acridines and an aromatic amine. It is a conjugate base of a tacrine(1+).
A centerally active cholinesterase inhibitor that has been used to counter the effects of muscle relaxants, as a respiratory stimulant, and in the treatment of Alzheimer's disease and other central nervous system disorders. Tacrine has been discontinued for the United States market.
Tacrine is a Cholinesterase Inhibitor. The mechanism of action of tacrine is as a Cholinesterase Inhibitor.
Tacrine is an oral acetylcholinesterase inhibitor previously used for therapy of Alzheimer disease. Tacrine therapy is associated with a very high rate of serum aminotransferase elevations during therapy and has been linked to several instances of clinically apparent, acute liver injury.
Tacrine is only found in individuals that have used or taken this drug. It is a centerally active cholinesterase inhibitor that has been used to counter the effects of muscle relaxants, as a respiratory stimulant, and in the treatment of Alzheimer's disease and other central nervous system disorders. The mechanism of tacrine is not fully known, but it is suggested that the drug is an anticholinesterase agent which reversibly binds with and inactivates cholinesterases. This inhibits the hydrolysis of acetylcholine released from functioning cholinergic neurons, thus leading to an accumulation of acetylcholine at cholinergic synapses. The result is a prolonged effect of acetylcholine.
A cholinesterase inhibitor that crosses the blood-brain barrier. Tacrine has been used to counter the effects of muscle relaxants, as a respiratory stimulant, and in the treatment of Alzheimer's disease and other central nervous system disorders.

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Drug Indication
For the palliative treatment of mild to moderate dementia of the Alzheimer's type.

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Mechanism of Action
The mechanism of tacrine is not fully known, but it is suggested that the drug is an anticholinesterase agent which reversibly binds with and inactivates cholinesterases. This inhibits the hydrolysis of acetylcholine released from functioning cholinergic neurons, thus leading to an accumulation of acetylcholine at cholinergic synapses. The result is a prolonged effect of acetylcholine.

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Pharmacodynamics
Tacrine is a parasympathomimetic- a reversible cholinesterase inhibitor that is indicated for the treatment of mild to moderate dementia of the Alzheimer's type. An early pathophysiological feature of Alzheimer's disease that is associated with memory loss and cognitive deficits is a deficiency of acetylcholine as a result of selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus. Tacrine is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine at cholinergic synapses through reversible inhibition of its hydrolysis by acetylcholinesterase. If this proposed mechanism of action is correct, tacrine's effect may lessen as the disease progresses and fewer cholinergic neurons remain functionally intact. There is no evidence that tacrine alters the course of the underlying dementing process.

C13H14N2

198.26366

198.115

321-64-2

1684-40-8 (hydrochloride)

1935

Off-white to light yellow solid powder

1.3±0.1 g/cm3

353.8±42.0 °C at 760 mmHg

283-284ºC

167.8±27.9 °C

0.0±0.8 mmHg at 25°C

1.682

1.78

1

2

0

15

229

0

YLJREFDVOIBQDA-UHFFFAOYSA-N

InChI=1S/C13H14N2/c14-13-9-5-1-3-7-11(9)15-12-8-4-2-6-10(12)13/h1,3,5,7H,2,4,6,8H2,(H2,14,15)

1,2,3,4-tetrahydroacridin-9-amine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~504.39 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.61 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (12.61 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: 2.5 mg/mL (12.61 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)