In the pregnant mouse, fluphenazine (1 mg/kg; IG) induces gestation from days 6 to 15 of gestation [5]. Piperidine resistance causes: Fluphenazine (0.125–1 mg/kg; IP, single dose)

Animal/Disease Models: Mice (injection of 60 mg/kg methylphenidate) [6]
Doses: 0.125, 0.25, 0.5, 1 mg/kg
Route of Administration: IP, single dose.
Experimental Results: Antagonizes stereotyped biting caused by methylphenidate; 0.0625-0.5 mg/kg Dramatically inhibits the climbing behavior of mice, and the dose of 1 mg/kg completely eliminates this effect.

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Animal/Disease Models: Mature female Swiss-Webster mice [5]
Doses: 1 mg/kg
Route of Administration: IG, treatment on the 6th to 15th day of pregnancy
Experimental Results: Fetal weight and length were Dramatically diminished, and the sternum and skull were incomplete. The incidence of ossification increases in the bone.

Absorption, Distribution and Excretion
Fluphenazine hydrochloride is rapidly absorbed from the gastrointestinal tract and parenteral routes. After oral or intramuscular administration, fluphenazine hydrochloride typically takes effect within 1 hour; the duration of action is 6-8 hours. In a small study, peak serum fluphenazine concentrations were reached within 1.5-2 hours and 0.5 hours, respectively, after a single intramuscular or oral injection.
Esterification of fluphenazine slows the rate of drug release from adipose tissue, thereby prolonging the duration of action; administration via sesame oil further delays the release rate. After intramuscular injection of decanoic acid fluphenazine dissolved in sesame oil, the onset of action is 24-72 hours; the duration of action is typically 1-6 weeks, with an average of 2 weeks.
Phenothiazines are highly bound to plasma proteins.
The distribution and metabolic pathways of fluphenazine are not fully elucidated. Fluphenazine has been reported to cross the blood-brain barrier; radioactivity was detected in the cerebrospinal fluid of two subjects after intramuscular injection of radiolabeled fluphenazine decanoate. For more complete data on the absorption, distribution, and excretion of fluphenazine (7 types), please visit the HSDB records page. Metabolites/Metabolites In dogs and rhesus monkeys, the major fecal metabolite 7-hydroxyfluphenazine has been isolated and identified by mass spectrometry and nuclear magnetic resonance measurements, involving synthetic 7- and 8-hydroxyfluphenazine. In the bile of treated dogs and rhesus monkeys, 7-hydroxyfluphenazine exists as a glucuronide. Degradation of the piperazine ring in vivo leads to the formation of γ-(phenothiazinyl-10)-propylamine and its ring-substituted analogues CF3-γ-(phenothiazinyl-10)-propylamine and C1-γ-(phenothiazinyl-10)-propylamine.
Fluphenazine and its major metabolites, including fluphenazine sulfoxide, 7-hydroxyfluphenazine, and fluphenazine conjugates, were detected in human plasma, urine, and feces after intramuscular and oral administration of 25 mg (14)C-fluphenazine dihydrochloride.
Adult and newborn rats were treated with psychotropic drugs; the researchers treated the animals with antipsychotic drugs (fluphenazine, beniralidol, pimozide, thiamethoxam), sedatives (oxazepam), and antidepressants (protriptyline) for one year or longer. During this period, the animals' body weight was monitored, and brain weight, total brain lipid content, phospholipid content, (32)P incorporation into each phospholipid, and fatty acid composition of phosphatidylethanolamine were measured. The results showed that long-term use of antipsychotic drugs and antidepressants (but not oxazepam) led to significant changes in phospholipid biochemistry, and these changes were generally biphasic or multiphasic. These variations should be considered when discussing the mechanisms of action and side effects of long-term antidepressants and antipsychotics. More complete metabolite/metabolite data for fluphenazine (6 metabolites) can be found on the HSDB record page. Known human metabolites of fluphenazine include 10-{3-[4-(2-hydroxyethyl)piperazin-1-yl]propyl}-2-(trifluoromethyl)-10H-5'-phenothiazin-5-one.

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Biological half-life
……The mean terminal half-life (± standard deviation) of fluphenazine is 16.4 ± 13.3 hours. ...
After a single oral dose of fluphenazine hydrochloride, the plasma half-life was 14.7 hours in one patient; after intramuscular injection of fluphenazine hydrochloride, the plasma half-lives were 14.9 hours and 15.3 hours in two patients, respectively. After intramuscular injection of fluphenazine enanthate, the plasma half-lives of the two patients were 3.6 days and 3.7 days, respectively; after intramuscular injection of fluphenazine decanoate, the plasma half-lives of the two patients were 9.6 days and 6.8 days, respectively.

Toxicity Summary
Fluphenazine blocks postsynaptic dopamine D1 and D2 receptors in the mesolimbic system of the brain; it inhibits the release of hypothalamic and pituitary hormones and is thought to inhibit the reticular activating system, thereby affecting basal metabolism, body temperature, arousal, vasomotor tone, and vomiting. Interactions
For patients receiving insulin therapy, it may be necessary to increase the insulin dose or decrease the chlorpromazine dose to maintain glycemic control… Other phenothiazines that may increase glycemic levels include fluphenazine…
Concomitant use of imipramine and chlorpromazine may result in elevated serum concentrations of one of the drugs…Chlorpromazine inhibits the metabolism of imipramine and nortriptyline. Similar precautions should be taken when using other phenothiazines concurrently… Phenothiazines
A 23-year-old male patient with bipolar disorder reported a drug interaction between ascorbic acid and fluphenazine hydrochloride. During 13 days of ascorbic acid replacement therapy, the patient's steady-state plasma concentration of fluphenazine hydrochloride decreased by 25% from baseline. This decrease in concentration is associated with the exacerbation of manic behavior. The mechanism by which ascorbic acid replacement therapy reduces the plasma concentration of fluphenazine hydrochloride may involve not only hepatic enzyme induction but also interactions during the absorption phase. Fluphenazine hydrochloride, along with other QT prolonging drugs including cisapride, erythromycin, and quinidine, may produce additive QT prolongation when used in combination with phenothiazines, increasing the risk of arrhythmias. /Phenothiazines/ For more complete data on interactions of fluphenazine (31 drugs in total), please visit the HSDB record page.

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Non-human toxicity values
Rat intraperitoneal LD50: 100 mg/kg
Rat subcutaneous LD50: 640 mg/kg
Mouse oral LD50: 220 mg/kg
Mouse intraperitoneal LD50: 89 mg/kg
Mouse intravenous LD50: 51 mg/kg

[1]. The neuroleptic drug, fluphenazine, blocks neuronal voltage-gated sodium channels. Brain Res. 2006;1106(1):72-81.

[2]. Based on Principles and Insights of COVID-19 Epidemiology, Genome Sequencing, and Pathogenesis: Retrospective Analysis of Sinigrin and ProlixinRX (Fluphenazine) Provides Off-Label Drug Candidates. SLAS Discov. 2020 Dec;25(10):1123-1140.

[3]. Siragusa S, Bistas KG, Saadabadi A. Fluphenazine. 2022 May 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan.

[4]. Peripheral diabetic neuropathy treated with amitriptyline and fluphenazine. JAMA. 1977 Nov 21;238(21):2291-2.

[5]. Teratogenic effect of diphenylhydantoin and/or fluphenazine in mice. J Appl Toxicol. 1996 May-Jun;16(3):221-5.

[6]. Langwiński R, Niedzielski J. Narcotic analgesics and stereotyped behaviour in mice. Naunyn Schmiedebergs Arch Pharmacol. 1980 Jul;312(3):225-7.

Therapeutic Uses
Antipsychotic, phenothiazines; dopamine antagonist. Fluphenazine hydrochloride is indicated for the treatment of manifestations of psychotic disorders. /US product label includes/ Fluphenazine hydrochloride has not been proven effective in treating behavioral complications in patients with intellectual disability. /US product label includes/ Individual variability in the response to antipsychotic medications may be caused by differences in patient adherence, interactions with other drugs, pharmacokinetic differences, and differences in receptor level concentration-response relationships. In some cases, pharmacokinetic differences can be compensated for by individualized dose adjustments based on plasma drug concentration measurements. Previously, differences in patient responses to specific time courses of drug concentration at receptor sites could only be assessed through clinical judgment. New methods for assessing receptor occupancy in vivo promise to measure parameters that at least partially explain individual variability in receptor level drug responses. Monitoring plasma concentrations of fluphenazine, perphenazine, thiothixol, and sulpiride using specific chemical analytical methods appears to provide some guidance for individualized drug dosing. Definite therapeutic plasma concentration ranges for chlorpromazine and haloperidol have not been established. However, when drug toxicity is suspected, monitoring plasma concentrations of chlorpromazine or haloperidol may be valuable and can be used as a means of controlling patient adherence. For more complete data on the therapeutic uses of fluphenazine (6 types), please visit the HSDB record page. Drug Warnings: /Fluphenazine/ Never administer intravenously. ...Extrapyramidal reactions...Quite common, usually of 3 types...Parkinsonian syndrome...Dystonia and dyskinesia, including torticollis, tics, and other involuntary muscle movements...Akasoriatic arthritis, manifested as restlessness...Hyperreflexia has been reported in newborns... /Phenothiazines/ Tardive dyskinesia developed in 12 patients aged 24 to 62 years after taking fluphenazine for 1–2 months to 10 years. Early symptoms of tardive dyskinesia are reversible, and the duration of symptoms before discontinuation is more important than age.
A patient with schizophrenia was admitted to the hospital two days after receiving an intramuscular injection of 50 mg fluphenazine heptahydrate. The abnormal secretion of antidiuretic hormone was likely related to the fluphenazine heptahydrate treatment. /Fluphenazine heptahydrate/
For more complete data on drug warnings for fluphenazine (47 total), please visit the HSDB records page.

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Pharmacodynamics
Fluphenazine is a trifluoromethylphenothiazine derivative used to treat schizophrenia and other psychotic disorders. Fluphenazine has not been shown to be effective in treating behavioral complications in patients with intellectual disability.

C22H26N3OF3S

437.5215

437.174

69-23-8

Fluphenazine-d8;1323633-98-2;Fluphenazine dihydrochloride;146-56-5;Fluphenazine dimaleate;3093-66-1

3372

Dark brown viscous oil

1.3±0.1 g/cm3

568.3±50.0 °C at 760 mmHg

268-274℃

297.5±30.1 °C

0.0±1.6 mmHg at 25°C

1.579

4.84

1

8

6

30

544

0

C1=CC=C2C(=C1)N(CCCN3CCN(CC3)CCO)C4=C(C=CC(=C4)C(F)(F)F)S2

PLDUPXSUYLZYBN-UHFFFAOYSA-N

InChI=1S/C22H26F3N3OS/c23-22(24,25)17-6-7-21-19(16-17)28(18-4-1-2-5-20(18)30-21)9-3-8-26-10-12-27(13-11-26)14-15-29/h1-2,4-7,16,29H,3,8-15H2

2-[4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]piperazin-1-yl]ethanol

FluphenazineTriflumethazineFluorophenazineFluorfenazineFluorphenazineSiqualine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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