Absorption, Distribution and Excretion
Following oral administration, prochlorperazine is reported to be well absorbed from the gastrointestinal tract. The onset of pharmacological action is about 30 to 40 minutes following oral administration and 10 to 20 minutes following intramuscular administration. The duration of action for all routes is about 3 to 4 hours. Following oral administration in healthy volunteers, the mean oral bioavailability was about 12.5%. In these patients, the time to reach the peak plasma concentrations was about 5 hours. Repeated oral dosing resulted in an accumulation of prochlorperazine and its metabolite. Following multiple twice daily dosing, the steady state of prochlorperazine was reached by 7 days.
Prochlorperazine is reported to be mainly excreted via the feces and bile. Low quantities of unchanged prochlorperazine and its metabolite were detectable in the urine.
In a preliminary pharmacokinetic study involving healthy volunteers, the mean apparent volume of distribution following intravenous administration of 6.25 mg and 12.5 mg prochlorperazine were approximately 1401 L and 1548 L, respectively. Prochlorperazine is reported to be distributed to most body tissues with high concentrations being distributed into liver and spleen. There is evidence that phenothiazines are excreted in the breast milk of nursing mothers.
The mean plasma clearance (CL) of prochlorperazine following intravenous administration in healthy volunteers was approximately 0.98L/h x kg. The mean renal clearance was about 23.6 mL/h.
Phenothiazines are generally well absorbed from the GI tract and from parenteral sites; however, absorption may be erratic, particularly following oral administration. Considerable interindividual variations in peak plasma concentrations have been reported. The variability may result from genetic differences in the rate of metabolism, biodegradation of the drug in the GI lumen, and/or metabolism of the drug during absorption (in the GI mucosa) and first pass through the liver.
Phenothiazines are highly bound to plasma proteins.
Phenothiazines and their metabolites are distributed into most body tissues and fluids, with high concentrations being distributed into the brain, lungs, liver, kidneys, and spleen. /Phenothiazine General Statement/
Phenothiazines readily cross the placenta. It is not known if the drugs are distributed into milk; however, the size of the molecules and their ability to readily cross the blood-brain barrier suggest that the drugs would be distributed into milk.
For more Absorption, Distribution and Excretion (Complete) data for Prochlorperazine (12 total), please visit the HSDB record page.

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Metabolism / Metabolites
Prochlorperazine undergoes hepatic metabolism involving oxidation, hydroxylation, demethylation, sulfoxide formation and conjugation with glucuronic acid. The oxidation reaction is mediated by CYP2D6. N-desmethyl prochlorperazine was detected in the plasma, as well as prochlorperazine sulfoxide, prochlorperazine 7-hydroxide and prochlorperazine sulfoxide 4'-N-oxide, following oral and buccal administration. Prochlorperazine may enter the enterohepatic circulation.
Most metabolites of phenothiazines are pharmacologically inactive; however, certain metabolites (eg, 7-hydroxychlorpromazine, mesoridazine) show moderate pharmacologic activity and may contribute to the action of the drugs. There is limited evidence to indicate that some phenothiazines (eg, chlorpromazine) may induce their own metabolism. /Phenothiazine General Statement/
Metabolized primarily in liver /by/ oxidation, hydroxylation, demethylation, sulfoxide formation and conjugation with glucuronic acid; metabolic alterations in side chain may also occur.
After chronic administration of piperazine-substituted phenothiazine drugs ... to rats, tissues contained drug metabolites, in which piperazine ring fission by multiple oxidative n-dealkylation had occurred to give substituted ethylenediamine. Thus, n-[gamma-(2-chlorphenothiazinyl-10)-propyl]ethylenediamine ... from prochlorperazine ...
Yields 2-chloro-10-(3-(4-methylpiperazin-1-yl)propyl)phenothiazine-n-oxide and 2-chloro-10-(3-(4-methylpiperazin-1-yl)propyl)phenothiazine sulfoxide in rats
For more Metabolism/Metabolites (Complete) data for Prochlorperazine (7 total), please visit the HSDB record page.
Hepatic. Undergoes metabolism in the gastric mucosa and on first pass through the liver, CYP2D6 and/or CYP3A4.
Half Life: 6 to 8 hours

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Biological Half-Life
Following intravenous and single oral dose administration, the terminal elimination half live were 9 and 8 hours, respectively.

Toxicity Summary
The mechanism of action of prochlorperazine has not been fully determined, but may be primarily related to its antidopaminergic effects. Prochlorperazine blocks the D2 somatodendritic autoreceptor, resulting in the blockade of postsynaptic dopamine receptors in the mesolimbic system and an increased dopamine turnover. Prochlorperazine also has anti-emetic effects, which can be attributed to dopamine blockade in the chemoreceptor trigger zone. Prochlorperazine also blocks anticholinergic and alpha-adrenergic receptors, the blockade of alpha(1)-adrenergic receptors resulting in sedation, muscle relaxation, and hypotension.

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Hepatotoxicity
Liver test abnormalities are uncommon during prochlorperazine therapy, perhaps because it is rarely given long term or in high doses chronically. Aminotransferase elevations can occur during therapy, but they are usually mild, asymptomatic and transient and reversible even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported due to prochlorperazine which resemble the cholestatic liver injury associated with chlorpromazine. The onset of jaundice is usually within 1 to 4 weeks, and the pattern of serum enzyme elevations is typically cholestatic or mixed. Immunoallergic features (fever and eosinophilia) occur in some cases, but they are usually mild and self-limited; autoantibodies are rare. Liver biopsy typically shows a cholestatic hepatitis. Importantly, prochlorperazine jaundice can be prolonged and has been associated with rare cases of vanishing bile duct syndrome (Case 1) that can be fatal or ultimately require liver transplantation.
Likelihood score: B (uncommon but likely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Based on minimal excretion of other phenothiazine derivatives, it appears that occasional short-term use of prochlorperazine for the treatment of nausea and vomiting poses little risk to the breastfed infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Galactorrhea has been reported with prochlorperazine. Hyperprolactinemia appears to be the cause of the galactorrhea.The hyperprolactinemia is caused by the drug's dopamine-blocking action in the tuberoinfundibular pathway.The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
There is limited data on protein binding of prochlorperazine.

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Toxicity Data
LD₅₀=400mg/kg (orally in mice)

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Interactions
Chlorpromazine and some other antipsychotic drugs ... may block antihypertensive effects of guanethidine. /Phenothiazines/
Chlorpromazine is used concurrently with meperidine to enhance its analgesic effect. ... Prochlorperazine...reported to interact with meperidine.
Benztropine is useless in treating tardive dyskinesia caused by chlorpromazine & possibility exists that it contributes to this adverse effect. ... Other phenothiazines associated with tardive dyskinesia including ... prochlorperazine. Similarly acting phenothiazines would be expected to have capability of producing dyskinesia.
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 Prochlorperazine (30 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 1800 mg/kg
LD50 Mouse oral 400 mg/kg
LD50 Mouse ip 120 mg/kg
LD50 Mouse sc 400 mg/kg

Therapeutic Uses
Antiemetics; Antipsychotic Agents, Phenothiazine; Dopamine Antagonists
/Prochlorperazine is indicated/ for control of severe nausea and vomiting. /Included in US product label/
/Prochlorperazine is indicated/ for the treatment of schizophrenia. /Included in US product label/
Prochlorperazine is effective for the short-term treatment of generalized non-psychotic anxiety. However, prochlorperazine is not the first drug to be used in therapy for most patients with non-psychotic anxiety, because certain risks associated with its use are not shared by common alternative treatments (eg, benzodiazepines). /Included in US product label/
For more Therapeutic Uses (Complete) data for Prochlorperazine (7 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Prochlorperazine maleate is not approved for the treatment of patients with dementia-related psychosis.
VET: Epinephrine may further lower, rather than elevate, blood pressures in animals on this phenothiazine derivatives.
Do not use in patients with known hypersensitivity to phenothiazines.
Do not use in comatose states or in the presence of large amounts of central nervous system depressants (alcohol, barbiturates, narcotics, etc.).
For more Drug Warnings (Complete) data for Prochlorperazine (53 total), please visit the HSDB record page.

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Pharmacodynamics
Prochlorperazine is an antipsychotic agent that works to promote postsynaptic inhibition of dopaminergic neurons. It also exerts its anti-emetic actions via anti-dopaminergic effects, where it displays similar efficacy as ondansteron, a 5HT-3 receptor antagonist and anti-emetic, in preventing delayed nausea and vomiting. Prochlorperazine was shown to inhibit histaminergic, cholinergic and alpha-1 adrenergic receptors. The blockade of alpha-1 adrenergic receptors may result in sedation, muscle relaxation, and hypotension. It displays anti-anxiety effects as well. Compared to other phenothiazine derivatives, prochlorperazine is less sedating and has a weak propensity for causing hypotension or potentiating the effects of CNS depressants and anesthetics. Other than its primary action on D2 receptors, one study showed that prochlorperazine may inhibit the P2X7 receptor in human macrophages, leading to inhibition of calcium ion influx.

373.9427

373.137

58-38-8

4917

Viscous liquid

1.2±0.1 g/cm3

524.8±50.0 °C at 760 mmHg

228 °C

271.2±30.1 °C

0.0±1.4 mmHg at 25°C

1.621

4.61

0

4

4

25

429

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])[H])C([H])([H])C1([H])[H]

WIKYUJGCLQQFNW-UHFFFAOYSA-N

InChI=1S/C20H24ClN3S/c1-22-11-13-23(14-12-22)9-4-10-24-17-5-2-3-6-19(17)25-20-8-7-16(21)15-18(20)24/h2-3,5-8,15H,4,9-14H2,1H3

2-chloro-10-[3-(4-methylpiperazin-1-yl)propyl]phenothiazine

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.)