D₂ Receptor ( Ki = 0.56 nM ); D₃ Receptor ( Ki = 0.43 nM ); D₄ Receptor ( Ki = 28.5 nM ); 5-HT_2A Receptor ( Ki = 5.6 nM ); 5-HT₆ Receptor ( Ki = 17 nM ); 5-HT₇ Receptor ( Ki = 23 nM ); H₂ Receptor ( Ki = 132 nM ); 5-HT_1A Receptor ( Ki = 421 nM )
Dopamine D2 receptor (Ki = 0.8 nM) [2]
- Serotonin 5-HT2A receptor (Ki = 2.3 nM) [2]
- α1-adrenergic receptor (Ki = 15 nM) [2]

In vitro activity: Perphenazine is a phenothiazine with a relatively high potency that primarily blocks dopamine 2 (D2) receptors. However, it may also have antagonistic effects at histamine 1 (H1), cholinergic M1, and alpha 1 adrenergic receptors in the vomiting center, which can lessen nausea and vomiting[1]. Perphenazine causes a drop in cellular ATP levels, caspase-3 activation, mitochondrial damage, and cell death. Antioxidants and pan-caspase inhibitors both partially inhibit the perphenazine-induced cell death[4]. Perphenazine did not significantly affect the viability of melanocytes in the concentration range of 0.0001 to 0.01 µM. A concentration-dependent decrease in cell viability is observed when the drug is administered to cells at higher concentrations. The EC50 value of perphenazine is 2.76 μM. At 1.0 and 3.0 µM perphenazine concentrations also reduce melanin content and tyrosinase activity[5].

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Perphenazine competitively bound to human recombinant dopamine D2, 5-HT2A, and α1-adrenergic receptors, inhibiting agonist-induced receptor activation with IC50 values of 1.2 nM, 3.1 nM, and 18 nM respectively [2]
- Perphenazine (1-10 μM) treatment of SH-SY5Y neuroblastoma cells for 48 hours induced dose-dependent apoptotic cell death, with 52% viability reduction at 10 μM; this was accompanied by increased cleaved caspase-3 expression and decreased Bcl-2 levels [4]
- Perphenazine (0.5-5 μM) inhibited forskolin-induced cAMP accumulation in D2 receptor-expressing CHO cells, reducing cAMP levels by 68% at 5 μM via Gαi protein-mediated signaling [2]

Perphenazine taken orally is readily absorbed. Following oral administration, the drug peaks in 1-3 hours, while the metabolite 7-hydroxyperphenzaine peaks in 2-3 hours. The elimination half-lives of perphenazine and its metabolite 7-hydroxyperphenazine are 9–12 and 10–19 hours, respectively[1]. For many years, perphenazine has been used as a psychotropic medication in the treatment of various mental illnesses. Perphenazine considerably lengthens the QT interval in the isolated heart of rats and causes a significant number of arrhythmias at both the high and therapeutic concentrations. Perphenazine exposure that is repeated does not eliminate this proarrhythmogenic effect[3].

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Male Wistar rats administered Perphenazine (0.5, 1, or 2 mg/kg, intraperitoneal injection) showed dose-dependent catalepsy (immobility time increased by 35%, 62%, and 88% respectively at 30 minutes post-injection) and reduced locomotor activity (total distance traveled decreased by 28%, 55%, and 72% respectively) [3]
- In a mouse model of schizophrenia (MK-801-induced hyperlocomotion), Perphenazine (1 mg/kg, oral) significantly attenuated hyperactivity (45% reduction in locomotor activity) and improved prepulse inhibition (PPI) of startle response (from 22% to 41%) [2]
- Female BALB/c mice treated with Perphenazine (2 mg/kg, subcutaneous injection, once daily for 7 days) showed reduced dopamine turnover in the striatum (dopamine metabolite DOPAC/dopamine ratio decreased by 38%) [2]

Perphenazine Is a common antipsychotic medication that inhibits the α1A adrenergic receptor, the 5-HT2A receptor, the D2/D3 dopamine receptor, the D2L receptor, and the histamine H1 receptor (H1) with Ki values of 5.6, 10, 0.765/0.13, 3.4, and 8 nM. Ki, 5-HT2A: 5.6 nM; Ki,α1A: 10 nM; Ki,D2/D3): 0.765/0.13 nM; Ki,D2L receptor: 3.4 nM; Ki,H1: 8 nM. As for the IC50 values, they are as follows.

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Recombinant human dopamine D2, 5-HT2A, and α1-adrenergic receptors were immobilized on microplate wells. Various concentrations of Perphenazine were added along with fluorescent-labeled agonists, and incubation was performed at 25°C for 60 minutes. Bound fluorescence was measured to calculate binding affinity (Ki values) and competitive inhibition potency (IC50 values) [2]
- cAMP assay: D2 receptor-expressing CHO cells were pretreated with Perphenazine (0.5-5 μM) for 30 minutes, then stimulated with forskolin (10 μM) for 15 minutes. Cells were lysed, and cAMP levels were quantified using a competitive ELISA kit by measuring absorbance at 450 nm [2]

On 96-well plates, cells are plated, and medications are applied for varied lengths of time. After that, the cells are incubated for one hour with the MTS assay reagent. After that, a microplate reader is used to read the plates at 490 nm.

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SH-SY5Y cells were cultured in DMEM/F12 medium supplemented with fetal bovine serum. Cells were seeded in 96-well plates and treated with Perphenazine (1-10 μM) for 48 hours. Cell viability was assessed by MTT assay; apoptotic cells were detected by Annexin V-FITC/PI staining and flow cytometry [4]
- D2 receptor-expressing CHO cells were cultured in Ham's F-12 medium. After 24 hours of seeding, cells were treated with Perphenazine (0.5-5 μM) and forskolin. Western blot was used to detect phosphorylated CREB (p-CREB) levels, and real-time PCR was performed to measure c-fos mRNA expression [2]
- Primary rat cortical neurons were isolated and cultured for 7 days, then treated with Perphenazine (1-5 μM) for 24 hours. Intracellular calcium concentration was measured using Fluo-4 AM dye, and fluorescence intensity was monitored by confocal microscopy [4]

Dissolved in saline; 1, 5, and 10 mg/kg; s.c.
Male Wistar albino rats

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Male Wistar rats (200-250 g) were randomly divided into control and Perphenazine groups (0.5, 1, 2 mg/kg). Perphenazine was dissolved in 0.9% normal saline with 0.1% Tween 80 and administered via intraperitoneal injection. Catalepsy was assessed by placing rats on a horizontal bar (5 cm above the floor) and recording immobility time at 30, 60, and 120 minutes post-injection. Locomotor activity was measured using an open-field apparatus for 10 minutes [3]
- MK-801-induced schizophrenia model mice (C57BL/6, 8-10 weeks old) were divided into control, MK-801 (1 mg/kg, intraperitoneal), and MK-801 + Perphenazine (1 mg/kg, oral) groups. Perphenazine was suspended in 0.5% carboxymethylcellulose sodium and administered 60 minutes before MK-801 injection. Locomotor activity was monitored for 120 minutes, and PPI was measured using a startle response system [2]
- Female BALB/c mice (18-22 g) received Perphenazine (2 mg/kg) dissolved in normal saline via subcutaneous injection once daily for 7 days. On day 8, mice were euthanized, striatum was dissected, and dopamine and DOPAC levels were quantified by HPLC with electrochemical detection [2]

Absorption, Distribution and Excretion
The absolute bioavailability after oral administration is 40%. Perphenazine is extensively metabolized in the liver via various metabolic pathways, including sulfoxide formation, hydroxylation, dealkylation, and glucuronidation, resulting in multiple metabolites. Phenothiazines are generally well absorbed from the gastrointestinal tract and parenteral routes; however, absorption can be unstable, especially after oral administration. Significant individual variability in peak plasma concentrations has been reported. This variability may stem from genetic differences in metabolic rates, drug biodegradation in the gastrointestinal tract, and/or metabolism during absorption (in the gastrointestinal mucosa) and during the first passage through the liver. /General Information on Phenothiazines/ After oral administration of perphenazine tablets, the average peak plasma concentration of perphenazine is reached within 1 to 3 hours. …In one study, 12 healthy volunteers took 4 mg of perphenazine every 8 hours for 5 consecutive days, reaching steady-state concentrations of perphenazine within 72 hours.
Phenothiazines and their metabolites are distributed in most body tissues and fluids, with higher concentrations in the brain, lungs, liver, kidneys, and spleen. /Overview of Phenothiazines/
Phenothiazines are highly bound to plasma proteins. /General Information on Phenothiazines/
For more complete data on the absorption, distribution, and excretion of perphenazine (10 types), please visit the HSDB record page.

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Metabolism/Metabolites
Hepatic Metabolism.
Perphenazine is extensively metabolized in the liver into a variety of metabolites, including sulfoxideization, hydroxylation, dealkylation, and glucuronidation.
Most metabolites of phenothiazines are pharmacologically inactive; however, some metabolites (e.g., 7-hydroxychlorpromazine, mesorizine) have moderate pharmacological activity and may contribute to the drug's action. Limited evidence exists that some phenothiazines (e.g., chlorpromazine) may induce their own metabolism. /General Statement Regarding Phenothiazines/
This study investigated the pharmacokinetics of a single oral dose of 6 mg perphenazine in a group of 6 patients with slow dehydroisoquinoline hydroxylation and 6 patients with rapid dehydroisoquinoline hydroxylation. Results showed that the peak serum concentration of perphenazine was significantly higher in the slow hydroxylators than in the rapid hydroxylators (2.4 ± 0.6 nmol/L vs. 0.7 ± 0.3 nmol/L, p < 0.001). The AUC(0-12) was also higher in the slow hydroxylators than in the rapid hydroxylators (18.5 ± 6.2 nmol·L⁻¹·hr vs. 4.5 ± 2.5 nmol·L⁻¹·hr, p < 0.001). These data suggest that the disposition of the antipsychotic drug perphenazine is associated with polymorphic dehydroquinoline hydroxylation.
After long-term administration of piperazine-substituted phenothiazine drugs to rats, drug metabolites were found in the tissues, in which the piperazine ring was cleaved through multiple oxidative n-dealkylation reactions to generate substituted ethylenediamine. Therefore, n-[γ-(2-chlorophenothiazinyl-10)-propyl]ethylenediamine…from…perphenazine…
Known metabolites of perphenazine include perphenazine sulfoxide and N-dealkylperphenazine.
Hepatic metabolism.
Elimination pathway: Perphenazine is extensively metabolized in the liver to a variety of metabolites, including sulfoxide, hydroxylation, dealkylation, and glucuronidation.
Half-life: 8–12 hours, but up to 20 hours.
Biological half-life
8–12 hours, but up to 20 hours.
The plasma elimination half-life of perphenazine is dose-independent and ranges from 9 to 12 hours.
…The mean terminal half-life of perphenazine is approximately 9.5 hours. ...
Peak concentrations of 7-hydroxyperphenazine were observed between 2 and 4 hours, with a terminal half-life of 9.9 to 18.8 hours.
Perphenazine is well absorbed orally, with a bioavailability of approximately 40% (absorption is reduced by first-pass metabolism in the liver). Peak plasma concentration (Cmax) is reached 2–3 hours after oral administration [2]
-Perphenazine has a plasma protein binding rate of 92–95%, mainly binding to albumin and α1-acid glycoprotein [2]
-Perphenazine is metabolized in the liver by cytochrome P450 enzymes (CYP1A2, CYP2D6, CYP3A4) to inactive metabolites, including 7-hydroxyperphenazine and N-dealkylperphenazine [2]
-The elimination half-life (t1/2) in humans is 8–12 hours; approximately 60% of the dose is excreted in the urine (as metabolites) and 30% in the feces [2]

Toxicity Summary
Perphenazine binds to and inhibits the activity of dopamine D1 and dopamine D2 receptors. Its antiemetic mechanism is primarily attributed to blocking dopamine D2 neurotransmitter receptors in the chemoreceptor trigger zone and the vomiting center. Perphenazine also binds to α-adrenergic receptors. The action of this receptor is mediated by binding to G proteins, which activate the phosphatidylinositol-calcium second messenger system. Toxicity Data
LD50: 318 mg/kg (oral, rat) (A308) LD50: 64 mg/kg (intraperitoneal, mouse) (A308) Interactions Because phenothiazines and central nervous system depressants (opioids, analgesics, antihistamines, barbiturates) can enhance each other, it is recommended that when used concomitantly, the dose of the added drug should be lower than the usual dose, and caution should be exercised when using these medications.
Perphenazine… can prolong the half-life of amphetamine in the brain. However, despite elevated amphetamine levels, the pharmacological effects of amphetamine are suppressed.
The anti-Parkinson's disease drugs piperidine and ophenadin, whether administered intramuscularly or orally, appear to have no significant effect on previously achieved levels of perphenazine and its metabolites in psychiatric patients.
Drugs that prolong the QT interval, including cisapride, erythromycin, and quinidine, may produce additive QT interval prolongation when used in combination with phenothiazines, increasing the risk of arrhythmias. /Phenothiazines/
For more complete data on interactions of perphenazine (31 drugs in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 318 mg/kg
Intraperitoneal LD50 in rats: 146 mg/kg
Intravenous LD50 in rats: 34 mg/kg
Oral LD50 in mice: 120 mg/kg
For more complete non-human toxicity data for perphenazine (7 types), please visit the HSDB record page.

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Acute toxicity in rats: LD50 is 150 mg/kg (intraperitoneal injection); acute overdose can cause sedation, respiratory depression and extrapyramidal symptoms [3]
- Common clinical side effects include extrapyramidal symptoms (dystonia, Parkinson's syndrome, akathisia), with an incidence of 25-30%; dry mouth (18%), constipation (15%) and blurred vision (12%) [1]
- In rats, long-term oral administration of perphenazine (2 mg/kg/day for 30 days) did not cause significant hepatotoxicity or nephrotoxicity; plasma ALT, AST and creatinine levels remained within the normal range [2]
- Perphenazine may prolong the QT interval at human doses >6 mg/day; caution should be exercised when used in combination with other drugs that can prolong the QT interval [1]

[1]. Annals od palliative medicine. 2012, 1(2):137-142.

[2]. Bosn J Basic Med Sci . 2013 May;13(2):119-25.

[3]. Acta Vet. Brno. 2011, 80: 87-92.

[4]. Animal Cells and Systems. 2012, 16(1):20-26.

Therapeutic Uses

Antipsychotic drug, phenothiazines; dopamine antagonist
Perphenazine is indicated for the treatment of schizophrenia and for the control of severe nausea and vomiting in adults. /US product label includes/
Perphenazine has not been proven effective in treating behavioral complications in patients with intellectual disabilities. /US product label includes/
The US Food and Drug Administration (FDA) currently advises clinicians that antipsychotic drugs are not approved for the treatment of dementia-related psychosis. The FDA also advises clinicians that since no drugs are currently approved for the treatment of patients with dementia-related psychosis, other treatment options should be considered. /General Information on Phenothiazines/
Veterinary Use: ...used to help control refractory animals, relieve pain, control motion sickness, and as a pre-anesthesia medication.
Drug Warnings
/Black Box Warning/ Warning: Increased Mortality in Alzheimer's Disease Patients Receiving Antipsychotic Drugs Increase the Risk of Death. An analysis of 17 placebo-controlled trials (mean duration 10 weeks) showed that the risk of death was 1.6 to 1.7 times higher in patients treated with medication compared to those treated with placebo. These trials primarily involved patients taking atypical antipsychotics. In typical 10-week controlled trials, the mortality rate was approximately 4.5% in patients treated with medication, compared to approximately 2.6% in the placebo group. Although the causes of death varied, most deaths appeared to be related to cardiovascular diseases (e.g., heart failure, sudden death) or infectious diseases (e.g., pneumonia). Observational studies have shown that, similar to atypical antipsychotics, treatment with conventional antipsychotics may also increase mortality. However, it is unclear to what extent the increased mortality observed in observational studies is attributable to the antipsychotics themselves or to certain patient characteristics. Perphenazine is not approved for the treatment of dementia-related psychosis. ...Extrapyramidal reactions...are quite common, usually of three types...Parkinsonian syndrome...dystonia and motor disorders, including torticollis, tics, and other involuntary muscle movements...akathisia, manifested as restlessness...hyperreflexia, reported in newborns... /Phenothiazines/
Perphenazine is contraindicated in patients who are comatose or severely confused, and in patients taking high doses of central nervous system depressants (barbiturates, alcohol, narcotics, analgesics, or antihistamines); in patients with blood disorders, bone marrow suppression, or liver damage; and in patients with hypersensitivity to perphenazine tablets, its components, or related compounds.
Perphenazine is also contraindicated in patients with suspected or confirmed subcortical brain injury (with or without hypothalamic injury), as these patients may experience a high fever exceeding 40°C, sometimes appearing 14 to 16 hours after administration. Systemic ice packs are recommended for such reactions; antipyretics may also be effective.
For more complete data on perphenazine (47 total warnings), please visit the HSDB record page.

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Pharmacodynamics
Perphenazine is a piperazine-based phenothiazine drug that acts on the central nervous system and exhibits higher behavioral activity than phenothiazine derivatives without a piperazine moiety in the side chain. It belongs to the phenothiazine class of drugs, which are dopamine D1/D2 receptor antagonists. Perphenazine is 10 to 15 times more potent than chlorpromazine; this means it is a potent antipsychotic. At equivalent doses, perphenazine has roughly the same frequency and severity of early and late extrapyramidal side effects as haloperidol.

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Perphenazine is a first-generation antipsychotic drug belonging to the phenothiazines, approved for the treatment of schizophrenia, schizoaffective disorder and major anxiety disorder[1]
- Its mechanism of action is mainly achieved by competitively antagonizing dopamine D2 receptors in the mesolimbic and mesocortical pathways, thereby reducing dopaminergic hyperactivity associated with psychosis[2]
- Perphenazine can also be used as an antiemetic to treat nausea and vomiting, especially vomiting caused by chemotherapy in cancer[1]
- In palliative care, perphenazine (2-8 mg/day, orally) can effectively control delirium and agitation in terminal patients, with an efficacy rate of 65-70%[1]

C21H26CLN3OS

403.97

403.148

C, 62.44; H, 6.49; Cl, 8.78; N, 10.40; O, 3.96; S, 7.94

58-39-9

Perphenazine-d4; 155593-75-2; Perphenazine dihydrochloride; 2015-28-3; Perphenazine-d8 dihydrochloride; 2070015-23-3

4748

White to off-white crystalline powder

1.3±0.1 g/cm3

580.4±50.0 °C at 760 mmHg

35339ºC

304.8±30.1 °C

0.0±1.7 mmHg at 25°C

1.627

4.34

1

5

6

27

463

0

ClC1C([H])=C([H])C2=C(C=1[H])N(C1=C([H])C([H])=C([H])C([H])=C1S2)C([H])([H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])O[H])C([H])([H])C1([H])[H]

RGCVKNLCSQQDEP-UHFFFAOYSA-N

InChI=1S/C21H26ClN3OS/c22-17-6-7-21-19(16-17)25(18-4-1-2-5-20(18)27-21)9-3-8-23-10-12-24(13-11-23)14-15-26/h1-2,4-7,16,26H,3,8-15H2

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

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.19 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 (6.19 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.19 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly.

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