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 GI tract and from parenteral sites. Following oral or im administration of fluphenazine hydrochloride, the onset of action usually occurs within 1 hour; the duration of action is 6-8 hours. Following administration of a single dose of fluphenazine hydrochloride in one limited study, peak serum fluphenazine concentrations were reached within 1.5-2 or 0.5 hours following im or oral administration, respectively.
Esterification of fluphenazine slows the rate of release of the drug from fatty tissues, thus prolonging the drug's duration of action; administration of the esters in a sesame oil vehicle further delays their rate of release. Following im administration of fluphenazine decanoate in sesame oil, the onset of action occurs within 24-72 hours; the duration of action is usually 1-6 weeks, with an average of 2 weeks.
Phenothiazines are highly bound to plasma proteins.
The distribution and metabolic fate of fluphenazine have not been fully elucidated. Fluphenazine reportedly crosses the blood-brain barrier; radioactivity was present in CSF following im administration of radiolabeled fluphenazine decanoate in 2 individuals.
For more Absorption, Distribution and Excretion (Complete) data for Fluphenazine (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
In dogs and rhesus monkeys, the major fecal metabolite, 7-hydroxyfluphenazine, was isolated and identified by mass spectrometric and NMR measurements, involving synthetic 7- and 8-hydroxyfluphenazines. 7-hydroxyfluphenazine is present in bile of treated dogs and rhesus monkeys as glucuronide.
Degradation of piperazine ring in fluphenazine in vivo leads to formation of gamma-(phenothiazinyl-10)-propylamine and of its ring substituted analogs CF3-gamma-(phenothiazinyl-10)-propylamine and C1-gamma-(phenothiazinyl-10)-propylamine.
Fluphenazine and its principal metabolites, fluphenazine sulfoxide, 7-hydroxyfluphenazine and fluphenazine conjugates were identified in human plasma, urine and feces, following im and oral administration of 25 mg of (14)C-fluphenazine dihydrochloride to patients.
Adult and newborn rats were treated with psychotropic drugs; neuroleptics (fluphenazine, benperidol, pimozide, thiotixen), an ataractic (oxazepam) and an anti- depressant (protriptyline) for periods up to one year or longer. The body weight was monitored, and brain weight, total cerebral lipid content, content of individual phospholipids, incorporation of (32)P into individual phospholipids, and the fatty acids composition of phosphatidylethanolamine were measured. The prolonged treatment with neuroleptics and an antidepressant, but not with oxazepam, produced profound, often biphasic or multiphasic changes in the biochemistry of phospholipids. These changes should be taken into account in discussion of the mechanism of action and side-effects of prolonged treatment with antidepressants and neuroleptics.
For more Metabolism/Metabolites (Complete) data for Fluphenazine (6 total), please visit the HSDB record page.
Fluphenazine has known human metabolites that 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 of fluphenazine (+ or - SD) was 16.4 + or - 13.3 hr. ...
Plasma half-life of fluphenazine after a single dose was 14.7 hours in 1 patient given hydrochloride by mouth and 14.9 and 15.3 hours in 2 patients given hydrochloride by intramuscular injection. Half-life was 3.6 and 3.7 days in 2 patients given enanthate intramuscularly and 9.6 and 6.8 days in 2 patients given the decanoate intramuscularly.

Toxicity Summary
Fluphenazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

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Interactions
An increase in insulin dosage or decrease in chlorpromazine dosage may be necessary to maintain control of blood glucose levels in patients receiving insulin ... Other phenothiazines that may increase blood glucose levels include fluphenazine ... .
Concurrent use of imipramine and chlorpromazine may result in increased serum levels of either drug. ... Chlorpromazine inhibits the metabolism of imipramine and nortriptyline. Similar precaution should be observed when other ... phenothiazines are used concurrently ... . /Phenothiazines/
A drug interaction involving ascorbic acid and fluphenazine hydrochloride was reported in a 23 yr old male manic depressive patient. During 13 days patient received replacement ascorbic acid steady state fluphenazine hydrochloride plasma levels declined 25% from baseline. This reduction was associated with escalation of manic behavior. Mechanism by which ascorbic acid replacement lowers fluphenazine hydrochloride plasma levels might involve not only liver enzyme induction but also interactions at the absorptive phase. /Fluphenazine hydrochloride/
QT interval-prolonging medications, including cisapride, erythromycin, and quinidine /may produce/ additive QT interval prolongation increasing the risk of developing cardiac arrhythmias when /concurrently administered with phenothiazines/. /Phenothiazines/
For more Interactions (Complete) data for Fluphenazine (31 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat ip 100 mg/kg
LD50 Rat sc 640 mg/kg
LD50 Mouse oral 220 mg/kg
LD50 Mouse ip 89 mg/kg
LD50 Mouse iv 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 Agents, Phenothiazine; Dopamine Antagonists
Fluphenazine hydrochloride is indicated in the management of manifestations of psychotic disorders. /Included in US product label/
Fluphenazine hydrochloride has not been shown effective in the management of behavioral complications in patients with mental retardation. /Included in US product label/
Variability in response to antipsychotic drug treatment may be caused by variable patient compliance, interactions with other drugs, pharmacokinetic variations and variations in concentration-response relationships at the receptor level. Pharmacokinetic variations may in some cases be compensated by individual dosage adjustments based on plasma drug level measurements. The interpatient variability in response to certain time-course of drug concentrations at the receptor site could hitherto only be assessed by clinical judgement. New methods for in vivo assessment of receptor occupancy hold promise for possible measurement of parameters accounting for at least part of the interindividual variation in drug response at the receptor level. Monitoring of fluphenazine, perphenazine, thiothixene and sulpiride plasma levels by specific chemical assay methods seems to offer some guidance to individualization of drug doses. Definite therapeutic plasma level ranges have not been established for chlorpromazine and haloperidol. However, monitoring plasma levels of chlorpromazine or haloperidol might be of value when drug-induced toxicity is suspected, and as a means of controlling patient compliance.
For more Therapeutic Uses (Complete) data for Fluphenazine (6 total), please visit the HSDB record page.

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Drug Warnings
/Fluphenazine/ should never be given intravenously.
... Extrapyramidal reactions ... fairly common, usually 3 types ... Parkinsonian-like syndrome ... dystonia and dyskinesia, including torticollis, tics, and other involuntary muscle movements ... akathisia, shown by restlessness ... hyperreflexia, reported in newborn ... ./Phenothiazines/
12 patients, 24-62 yr old, developed tardive dyskinesia after receiving fluphenazine from 1-2 months to 10 years. First signs of tardive dyskinesia are reversible and length of time symptoms persist prior to discontinuing is more important than age.
Inappropriate antidiuretic hormone secretion most likely related with fluphenazine enanthate therapy in schizophrenic patient 2 days following im dose of 50 mg patient was admitted to hospital. /Fluphenazine Enanthate/
For more Drug Warnings (Complete) data for Fluphenazine (47 total), please visit the HSDB record page.

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Pharmacodynamics
Fluphenazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Fluphenazine has not been shown effective in the management of behaviorial complications in patients with mental retardation.

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.)