4-[3-[(Z)-2-(トリフルオロメチル)-9H-チオキサンテン-9-イリデン]プロピル]-1-ピペラジンエタノール

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

Pharmaceuticals -> Nervous system -> Antipsychotics

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P270, P271, P280, P301+P317, P302+P352, P304+P340, P317, P321, P330, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 38 reports by companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

Acute Tox. 4 (100%)

Acute Tox. 4 (100%)

Flupenthixol is a thioxanthene antipsychotic. The mechanism of action of Flupenthixol is not completely understood. Flupenthixol is a powerful antagonist of both D1 and D2 dopamine receptors, and an alpha-adrenergic receptor antagonist. It's antipsychotic activity is thought to be related to blocks postsynaptic dopamine receptors in the CNS.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

FLUPENTIXOL

DILI Positive

Oral, Intramuscular

DOI:10.1016/j.drudis.2019.09.022

N - Nervous system

QN - Nervous system

Flupentixol is an antipsychotic agent with anxiolytic and mild sedative actions. It exerts weak anticholinergic and adrenergic effects. It possesses antiemetic actions. As flupentixol works by antagonizing dopamine actions, it can cause extrapyramidal effects, mostly at doses greater than 10 mg. In clinical trials, flupentixol-induced extrapyramidal effects have been managed with anti-Parkinsonian drugs. Drug esterification in the intramuscular formulation of the drug results in slow release of the drug from the injection site and a prolonged duration of action. Flupentixol has been investigated for use in mild to moderate depression: compared to other antidepressant agents, flupentixol has a rapid onset of action, where antidepressive effects were observed within the first two to three days after administration. As with other antipsychotic agents, flupentixol can cause QTc prolongation and increase the risk of arrhythmias. In clinical trials, flupentixol was associated with the risk of cardiovascular disease, cerebrovascular adverse events, stroke, and venous thromboembolism. Flupentixol can elevate the levels of prolactin; however, the clinical significance of hyperprolactinemia caused by neuroleptic drugs is unclear. Long-term hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone mineral density in both female and male subjects. Interestingly, recent studies show that flupentixol exhibits anti-tumour properties alone or synergistically with other anticancer drugs like gefitinib. One study demonstrated that _in vitro_, flupentixol docks to the ATP binding pocket of phosphatidylinositol 3-kinase (PI3K), a lipid kinase that activates signalling pathways that are often hyperactivated in some cancers. Flupentixol inhibited the PI3K/AKT pathway and survival of lung cancer cells _in vitro_ and _in vivo_.

The mechanism of action of flupentixol is not completely understood. The antipsychotic actions are mainly thought to arise from cis(Z)-flupentixol, the active stereoisomer, acting as an antagonist at both dopamine D₁ and D₂ receptors with equal affinities. Schizophrenia is a mental illness characterized by positive (such as hallucinations and delusions) and negative (such as affect flattening and apathy) symptoms. While several neurotransmitter systems are implicated in the pathophysiologic processes leading to the development of symptoms, the dopamine and glutamate systems have been extensively studied. It is generally understood that positive symptoms of schizophrenia arise from a dysregulated striatal dopamine pathway, leading to hyperstimulation of D₂ receptors. Many antipsychotic agents work by blocking D₂ receptors as antagonists; similarly, cis(Z)-flupentixol, the active stereoisomer, is an antagonist at D₂ receptors. However, there is now evidence that antipsychotic agents can work by blocking other dopamine receptor subtypes, such as D₁, D₃, or D₄ receptors. One study showed that cis(Z)-flupentixol is an antagonist at both dopamine D₁ and D₂ receptors with equal affinities, and binds to D3 and D4 receptors with lower affinities. It also binds to alpha-1 adrenoceptors. Antidepressant effects of flupentixol are understood to be mediated by antagonism at 5-HT_2A receptors, which are commonly downregulated following repeated antidepressant treatment. Flupentixol also binds to 5-HT_2C receptors.

Flupentixol is metabolized in the liver via sulfoxidation, dealkylation, and glucuronidation to form pharmacologically inactive metabolites. Flupentixol decanoate, the active ingredient in the intramuscular formulation, is hydrolyzed to flupentixol.

Mainly hepatic Half Life: 19 to 39 hours

Following oral administration, flupentixol is readily absorbed from the gastrointestinal tract, with oral bioavailability of about 40%. Tmax ranges from three to eight hours. Steady-state plasma levels are achieved in about seven days and following once-daily oral administration of 5 mg flupentixol, the mean minimum steady-state level was about 1.7 ng/mL (3.9 nmol/L). From the site of intramuscular injection, esterified flupentixol diffuses slowly from the oil solution and is slowly released into the extracellular fluid and the circulation to be distributed to different tissues. Peak drug concentrations are reached between four and seven days following intramuscular injection. Intramuscularly administered flupentixol is detectable in the blood three weeks after injection and reaches steady-state concentrations after about three months of repeated administration.

Fecal excretion is more predominant than renal excretion. In the feces, flupentixol is recovered in the feces mainly as the unchanged form, as well as its lipophilic metabolites, such as dealkyl-flupentixol. Flupentixol is recovered in the urine as the unchanged form as well as its hydrophilic sulfoxide and glucuronide metabolites.

The apparent volume of distribution is about 14.1 L/kg. Following administration, the highest levels of flupentixol are found in the lungs, liver, and spleen. Lower concentrations of the drug are found in the blood and brain.

Following oral administration, the mean systemic clearance is about 0.29 L/min.

Use (kg; approx.) in Germany (2009): >50

For use in the treatment of schizophrenia and depression