Absorption, Distribution and Excretion
Tacrine is rapidly absorbed. The absolute bioavailability of tacrine is approximately 17%. 349 ± 193 L/h Metabolism/Metabolites Hepatic metabolism. Cytochrome P450 1A2 is the major isoenzyme involved in tacrine metabolism. The major metabolite, 1-hydroxytacrine (Venacrine), has central cholinergic activity. Known metabolites of tacrine include 4-hydroxytacrine, N4-hydroxylamine, 2-hydroxytacrine, and 7-hydroxytacrine. Hepatic metabolism. Cytochrome P450 1A2 is the major isoenzyme involved in tacrine metabolism. The major metabolite, 1-hydroxytacrine (Venacrine), has central cholinergic activity. Half-life: 2 to 4 hours. Biological half-life 2 to 4 hours

Toxicity Summary
Tacrine is a cholinesterase, or acetylcholinesterase (AChE) inhibitor. Cholinesterase inhibitors (or "anticholinesterases") inhibit the activity of acetylcholinesterase. Because acetylcholinesterase has important physiological functions, chemicals that interfere with its activity are potent neurotoxins; even low doses can cause excessive salivation and lacrimation, followed by muscle spasms, ultimately leading to death. Substances used in nerve gases and many pesticides have been shown to work by binding to serine residues at the active site of acetylcholinesterase, thus completely inhibiting the enzyme's activity. Acetylcholinesterase breaks down the neurotransmitter acetylcholine, which is released at the neuromuscular junction, causing muscle or organ relaxation. Inhibition of acetylcholinesterase results in the accumulation and sustained action of acetylcholine, leading to the continuous transmission of nerve impulses and the inability to stop muscle contractions. The most common acetylcholinesterase inhibitors are phosphorus-containing compounds, which are designed to bind to the enzyme's active site. Its structural requirements include a phosphorus atom with two lipophilic groups, a leaving group (e.g., a halide or thiocyanate), and a terminal oxygen atom.
Hepatotoxicity
Notably, nearly half of patients treated with tacrine experienced elevated serum transaminase levels. These elevations typically appear within 6 to 8 weeks of starting treatment and rapidly return to normal upon discontinuation. 25% of patients had transaminase elevations exceeding 3 times the upper limit of normal (ULN), 6% exceeded 10 times the ULN, and 2% exceeded 20 times the ULN. Elevated alkaline phosphatase and bilirubin levels are rare; ALT abnormalities are usually asymptomatic and return to normal rapidly upon discontinuation or dose reduction. Monitoring serum transaminase levels is recommended during tacrine treatment. Dose adjustment is necessary if ALT elevation exceeds 3 times the ULN, and discontinuation is necessary if it exceeds 5 times the ULN. No cases of clinically significant acute liver injury with jaundice were reported in premarketing studies. However, several cases of acute hepatocellular injury with jaundice caused by taclin have been reported subsequently, usually appearing within 2 to 8 weeks after the start of treatment and typically resolving rapidly upon discontinuation of the drug. Eosinophilia often accompanies taclin-induced liver injury, but rash, fever, and autoantibodies are uncommon. Re-administration of the drug often leads to recurrence of liver injury, with a slightly shorter latency period but a similar or milder course. Many patients experience spontaneous resolution of elevated serum transaminases even without discontinuation or dose adjustment. However, the sponsor has received reports of several fatal liver injuries caused by taclin. Routine monitoring of serum transaminase levels is recommended during the first six months of treatment. However, because other oral anticholinesterase inhibitors only require once or twice daily, do not require ALT monitoring, and rarely cause elevated liver enzymes, taclin has been discontinued in clinical use in the United States.
Probability Score: A (Etiology of established liver injury, although usually presenting as elevated serum transaminases, but asymptomatic or without jaundice).
Protein Binding Rate
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 an acridine compound with the structure 1,2,3,4-tetrahydroacrine substituted with an amino group at the 9-position. It is used to treat Alzheimer's disease. Tacrine is an EC 3.1.1.7 (acetylcholinesterase) inhibitor. Tacrine belongs to the acridine and aromatic amine classes. It is the conjugate base of tacrine(1+). Tacrine is a centrally active cholinesterase inhibitor and has been used to antagonize the effects of muscle relaxants, as a respiratory stimulant, and to treat Alzheimer's disease and other central nervous system disorders. Tacrine is discontinued in the United States. Tacrine is a cholinesterase inhibitor. The mechanism of action of tacrine is as a cholinesterase inhibitor. Tacrine is an oral acetylcholinesterase inhibitor and has been used to treat Alzheimer's disease. Serum transaminase elevation rates are extremely high during tacrine treatment and have been associated with several clinically significant cases of acute liver injury. Tacrine is only present in individuals who have used or taken the drug. It is a centrally active cholinesterase inhibitor, previously used to counteract the effects of muscle relaxants, as a respiratory stimulant, and to treat Alzheimer's disease and other central nervous system disorders. The mechanism of action of tacrine is not fully understood, but studies suggest that it is an anticholinesterase agent that reversibly binds to and inactivates cholinesterase. This inhibits the hydrolysis of acetylcholine released from functional cholinergic neurons, leading to the accumulation of acetylcholine at cholinergic synapses. The result is a prolonged duration of acetylcholine's effect.
A cholinesterase inhibitor capable of crossing the blood-brain barrier. Tacrine has been used to counteract the effects of muscle relaxants, as a respiratory stimulant, and to treat Alzheimer's disease and other central nervous system disorders.
Indications
For the relief of mild to moderate Alzheimer's disease-related dementia.
Mechanism of Action
The mechanism of action of tacrine is not fully understood, but studies suggest that it is an anticholinesterase agent that reversibly binds to and inactivates cholinesterase. This inhibits the hydrolysis of acetylcholine released by functional cholinergic neurons, leading to the accumulation of acetylcholine at cholinergic synapses. The result is a prolonged effect of acetylcholine.

---

Pharmacodynamics
Tacrine is a parasympathomimetic drug, belonging to the class of reversible cholinesterase inhibitors, indicated for the treatment of mild to moderate Alzheimer's disease. One of the early pathophysiological features of Alzheimer's disease is acetylcholine deficiency, which is associated with memory loss and cognitive impairment. This deficiency is due to the selective loss of cholinergic neurons in the cerebral cortex, basal ganglia, and hippocampus. It is hypothesized that tacrine exerts its therapeutic effect by enhancing cholinergic function. This is achieved by reversibly inhibiting the hydrolysis of acetylcholine by acetylcholinesterase, thereby increasing the concentration of acetylcholine at cholinergic synapses. If this mechanism of action is correct, the efficacy of tacrine may diminish as the disease progresses and the number of functional cholinergic neurons decreases. There is no evidence that tacrine alters the underlying course of dementia.

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.

---

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.

---

View More

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.

---

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