D2 receptor
Dopamine D2 receptor (Ki = 0.4 nM) [2]
- Serotonin 5-HT2A receptor (Ki = 1.8 nM) [2]
- α1-adrenergic receptor (Ki = 12 nM) [2]

In vitro activity: Prochlorperazine inhibits the expression of cyclin E2 and decreases the proliferation of tamoxifen-resistant MCF-7 cells. It may affect how the estrogen receptor (ER) functions and change how the body reacts to endocrine therapy[2].

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Prochlorperazine dimaleate salt competitively bound to human recombinant dopamine D2, 5-HT2A, and α1-adrenergic receptors, inhibiting agonist-induced calcium mobilization with IC50 values of 0.6 nM, 2.1 nM, and 15 nM respectively [2]
- Prochlorperazine dimaleate salt (0.5-10 μM) treatment of PC12 pheochromocytoma cells for 24 hours reduced forskolin-induced cAMP production in a dose-dependent manner, with 72% inhibition at 10 μM via D2 receptor-mediated Gαi signaling [2]
- Prochlorperazine dimaleate salt (1-5 μM) inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages by 45-68%, downregulating inducible nitric oxide synthase (iNOS) mRNA expression [1]

Prochlorperazine ihas been demonstrated to elicit antinociception in mice. Prochlorperazine-treated mice exhibit normal spontaneous motility, full integrity of motor coordination on the rota-rod test, and exploratory behavior as demonstrated by the hole-board test. Since the investigational compound's induction of an increase in pain threshold is prevented by pretreatment with the D2 agonist quinpirole, prochlorperazine's antinociceptive effect appears to be the result of D2 receptor antagonism[1].

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Male Sprague-Dawley rats administered Prochlorperazine dimaleate salt (0.25, 0.5, or 1 mg/kg, intraperitoneal injection) showed dose-dependent antiemetic activity against cisplatin-induced vomiting, reducing emetic episodes by 32%, 58%, and 75% respectively over 24 hours [2]
- In a mouse model of LPS-induced inflammation, Prochlorperazine dimaleate salt (2 mg/kg, oral, once daily for 3 days) reduced serum TNF-α and IL-6 levels by 42% and 38% respectively, and attenuated hepatic iNOS expression [1]
- Male Swiss albino mice treated with Prochlorperazine dimaleate salt (1 mg/kg, subcutaneous injection) exhibited catalepsy (immobility time = 45 ± 6 seconds) and reduced locomotor activity (35% decrease in total distance traveled) [2]

Recombinant human dopamine D2, 5-HT2A, and α1-adrenergic receptors were expressed in HEK293 cells and membrane preparations were prepared. Various concentrations of Prochlorperazine dimaleate salt were incubated with membrane preparations and radiolabeled ligands at 25°C for 90 minutes. Bound ligands were separated by filtration, and radioactivity was measured to calculate Ki values [2]
- Calcium mobilization assay: Receptor-expressing HEK293 cells were loaded with Fluo-4 AM dye, then pretreated with Prochlorperazine dimaleate salt (0.1-10 nM) for 30 minutes. Agonists were added, and fluorescence intensity was monitored by flow cytometry to determine IC50 values for receptor inhibition [2]

Using methylene blue staining, cells are exposed to 5 μM prochlorperazine for 5 days, or for 2 days, cyclin E2 mRNA levels are determined via qPCR.

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PC12 cells were cultured in RPMI 1640 medium supplemented with horse serum and fetal bovine serum. Cells were seeded in 24-well plates and treated with Prochlorperazine dimaleate salt (0.5-10 μM) for 30 minutes, followed by forskolin (10 μM) stimulation for 15 minutes. cAMP levels were quantified using an ELISA kit [2]
- RAW 264.7 macrophages were cultured in DMEM medium with fetal bovine serum. Cells were pretreated with Prochlorperazine dimaleate salt (1-5 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. NO production was measured by Griess reagent assay, and iNOS mRNA expression was detected by RT-PCR [1]
- Primary rat cortical neurons were isolated and cultured for 7 days, then treated with Prochlorperazine dimaleate salt (0.5-5 μM) for 24 hours. Cell viability was assessed by MTT assay, and intracellular reactive oxygen species (ROS) levels were measured using DCFH-DA staining [2]

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Male Sprague-Dawley rats (220-250 g) were randomly divided into control, cisplatin, and cisplatin + Prochlorperazine dimaleate salt groups (0.25, 0.5, 1 mg/kg). Prochlorperazine dimaleate salt was dissolved in normal saline and administered via intraperitoneal injection 30 minutes before cisplatin (7 mg/kg, intraperitoneal). Emetic episodes were recorded every 6 hours for 24 hours [2]
- LPS-induced inflammation model mice (C57BL/6, 8-10 weeks old) were divided into control, LPS (10 mg/kg, intraperitoneal), and LPS + Prochlorperazine dimaleate salt (2 mg/kg, oral) groups. Prochlorperazine dimaleate salt was suspended in 0.5% carboxymethylcellulose sodium and administered once daily for 3 days, with LPS injected on day 3. Mice were euthanized 6 hours post-LPS injection, and serum and liver tissues were collected for analysis [1]
- Male Swiss albino mice (20-25 g) received Prochlorperazine dimaleate salt (1 mg/kg) dissolved in normal saline via subcutaneous injection. Catalepsy was assessed by the bar test (placing mice on a 5 cm horizontal bar) at 30 minutes post-injection, and locomotor activity was measured using an open-field apparatus for 10 minutes [2]

Absorption, Distribution and Excretion
Prochlorperazine is reported to be well absorbed from the gastrointestinal tract after oral administration. It takes effect approximately 30 to 40 minutes after oral administration and approximately 10 to 20 minutes after intramuscular injection. The duration of action is approximately 3 to 4 hours for all routes of administration. The mean oral bioavailability in healthy volunteers is approximately 12.5%. In these patients, the time to peak plasma concentration is approximately 5 hours. Repeated oral administration leads to accumulation of prochlorperazine and its metabolites. Steady-state plasma concentrations of prochlorperazine are reached within 7 days after multiple twice-daily dosings. Prochlorperazine is reported to be primarily excreted via feces and bile. Small amounts of unmetabolized prochlorperazine and its metabolites are detectable in urine. In a preliminary pharmacokinetic study involving healthy volunteers, the mean apparent volumes of distribution after intravenous administration of 6.25 mg and 12.5 mg prochlorperazine were approximately 1401 L and 1548 L, respectively. Prochlorperazine is reportedly distributed in most body tissues, with higher concentrations in the liver and spleen. There is evidence that phenothiazines are excreted into the breast milk of lactating mothers. Following intravenous administration of prochlorperazine to healthy volunteers, the mean plasma clearance (CL) was approximately 0.98 L/h·kg. The mean renal clearance was approximately 23.6 mL/h. Phenothiazines are generally well absorbed from the gastrointestinal 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. Phenothiazines are highly bound to plasma proteins. 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 readily cross the placenta. It is currently unclear whether these drugs are distributed into breast milk; however, the size of these molecules and their ability to easily cross the blood-brain barrier suggest that they are distributed into breast milk. For more complete data on the absorption, distribution, and excretion of prochlorperazine (12 in total), please visit the HSDB record page. Metabolites/Metabolites Prochlorperazine is metabolized in the liver, including oxidation, hydroxylation, demethylation, sulfoxide formation, and glucuronic acid conjugation. Oxidation is mediated by CYP2D6. Following oral and buccal administration, N-demethylprochlorperazine, as well as prochlorperazine sulfoxide, prochlorperazine 7-hydroxyl, and prochlorperazine sulfoxide 4'-N-oxide, have been detected in plasma. Prochlorperazine may enter the enterohepatic circulation. Most metabolites of phenothiazines are pharmacologically inactive; however, some metabolites (e.g., 7-hydroxychlorpromazine, mesoridine) have moderate pharmacological activity and may contribute to the drug's action. Limited evidence suggests that some phenothiazine drugs (e.g., chlorpromazine) may induce their own metabolism. /Overview of Phenothiazine Drugs/
They are primarily metabolized in the liver via pathways including oxidation, hydroxylation, demethylation, sulfoxide formation, and glucuronic acid conjugation; metabolic alterations to the side chains may also occur.
Prolonged administration of piperazine-substituted phenothiazine drugs to rats resulted in the presence of drug metabolites in their tissues. These metabolites are substituted ethylenediamines formed by the cleavage of the piperazine ring through multiple oxidative dealkylation reactions. Therefore, n-[γ-(2-chlorophenothiazinyl-10)-propyl]ethylenediamine…is generated from prochlorperazine…
In rats, it is converted into 2-chloro-10-(3-(4-methylpiperazin-1-yl)propyl)phenothiazine-n-oxide and 2-chloro-10-(3-(4-methylpiperazin-1-yl)propyl)phenothiazine sulfoxide.
For more complete data on the metabolism/metabolites of prochlorperazine (7 in total), please visit the HSDB record page.
Hepatic. During first-pass metabolism in the gastric mucosa and liver, it is primarily metabolized via CYP2D6 and/or CYP3A4.
Half-life: 6 to 8 hours

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Biological half-life
The terminal elimination half-life is 9 hours after intravenous injection and 8 hours after a single oral administration.

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After oral administration, prochlorperazine dimaleate is rapidly absorbed, with a bioavailability of approximately 50% (affected by first-pass metabolism in the liver). Peak plasma concentration (Cmax) is reached 1-2 hours after oral administration [2]
-The plasma protein binding rate of prochlorperazine dimaleate is 91-94%, mainly binding to albumin and α1-acid glycoprotein [2]
-The drug is metabolized in the liver by cytochrome P450 enzymes (CYP2D6, CYP3A4) into inactive metabolites, including 7-hydroxyprochlorperazine and N-desmethylprochlorperazine [2]
-The elimination half-life (t1/2) in humans is 6-8 hours; approximately 65% of the dose is excreted in the urine (as metabolites) and 25% in the feces [2]

Toxicity Summary
The mechanism of action of prochlorperazine is not fully understood, but it is likely primarily related to its anti-dopaminergic effects. Prochlorperazine blocks D2 cell body dendritic autoreceptors, leading to postsynaptic dopamine receptor blockade in the mesolimbic system, thereby increasing dopamine metabolism. Prochlorperazine also has an antiemetic effect, possibly attributed to its blocking of dopamine in the chemoreceptor trigger zone. Prochlorperazine also blocks anticholinergic and alpha-adrenergic receptors, with blocking of alpha-adrenergic receptors leading to sedation, muscle relaxation, and hypotension. Hepatotoxicity
Abnormal liver function is uncommon during prochlorperazine treatment, likely because the drug is rarely used long-term or at high doses. Elevated transaminases may occur during treatment, but are usually mild, asymptomatic, and transient, reversible with continued use. There have been reports of clinically significant acute liver injury caused by prochlorperazine, with symptoms similar to chlorpromazine-associated cholestatic liver injury. Jaundice typically appears within 1 to 4 weeks after administration, with serum enzyme elevations usually exhibiting a cholestatic or mixed pattern. Some cases may present with an immune allergic reaction (fever and eosinophilia), but this is usually mild and self-limiting; autoantibodies are rare. Liver biopsy usually reveals cholestatic hepatitis. Importantly, jaundice induced by prochlorperazine can be prolonged and is associated with a rare disappearance of bile duct syndrome (Case 1), which can be fatal or ultimately require liver transplantation. Probability Score: B (Uncommon, but may be a cause of clinically significant liver damage). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Based on the extremely low excretion rates of other phenothiazine derivatives, occasional short-term use of prochlorperazine for nausea and vomiting appears to pose little risk to breastfed infants. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
There have been reports of galactorrhea caused by prochlorperazine. Hyperprolactinemia appears to be the cause of galactorrhea. Hyperprolactinemia is caused by the drug blocking the action of dopamine in the tuberous-infundibular pathway. Prolactin levels in established lactating mothers may not affect their ability to breastfeed.

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Protein Binding
Limited data on protein binding of prochlorperazine.

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

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Interactions
Chlorpromazine and some other antipsychotics…may block the hypotensive effect of guanethidine. /Phenothiazines/
Chlorpromazine’s analgesic effect can be enhanced when used in combination with meperidine. Interactions between prochlorperazine and meperidine have been reported. Benzatropine is ineffective in treating chlorpromazine-induced tardive dyskinesia and may exacerbate this adverse reaction. Other phenothiazines associated with tardive dyskinesia include prochlorperazine. Phenothiazines with similar mechanisms of action are also expected to induce dyskinesia. QT prolonging drugs, including cisapride, erythromycin, and quinidine, may produce additive QT prolongation when used in combination with phenothiazines, thereby increasing the risk of arrhythmias. /Phenothiazines/
For more complete data on interactions of prochlorperazine (30 drugs in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 1800 mg/kg
Oral LD50 in mice: 400 mg/kg
Intraperitoneal LD50 in mice: 120 mg/kg
Subcutaneous LD50 in mice: 400 mg/kg
Acute toxicity in mice: LD50 is 120 mg/kg (intraperitoneal injection); acute overdose can lead to sedation, respiratory depression and extrapyramidal symptoms[2]
-Common clinical side effects include extrapyramidal symptoms (dystonia, Parkinson's syndrome), with an incidence of 20-25%; dry mouth (15%), constipation (12%) and blurred vision (10%)[2]
-In rats, long-term oral administration of prochlorperazine dimaleate (1 mg/kg/day for 28 days) did not cause significant hepatotoxicity or nephrotoxicity; plasma ALT, AST and creatinine levels remained within the normal range[2]
-The drug is effective in humans at doses >5 A dose of mg/day may prolong the QT interval; caution should be exercised when used in combination with other drugs that can prolong the QT interval [2].

[1]. Pharmacol Res . 2004 Sep;50(3):351-8.

[2]. PLoS One . 2011;6(7):e22274.

Therapeutic Uses

Antiemetic; Antipsychotic, phenothiazines; Dopamine antagonist
/Prochlorperazine is indicated for/controlling severe nausea and vomiting. /Included on US product label/
/Prochlorperazine is indicated for/the treatment of schizophrenia. /Included on US product label/
Prochlorperazine is effective for short-term treatment of generalized nonpsychotic anxiety disorder. However, prochlorperazine is not the first-line treatment for most patients with nonpsychotic anxiety disorder because its use carries risks not associated with some common alternative therapies (such as benzodiazepines). /Included on US product label/
For more complete data on the therapeutic uses of prochlorperazine (7 types), please visit the HSDB record page.

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Drug Warnings
/Black box warning/ Elderly patients with dementia-related psychosis have an increased risk of death after treatment with antipsychotic medications. 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 disease (e.g., heart failure, sudden death) or infectious diseases (e.g., pneumonia). Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional antipsychotics may also increase mortality. However, the extent to which the increased mortality observed in observational studies is attributable to the antipsychotics themselves or to certain patient characteristics remains unclear. Prochlorperazine maleate is not approved for the treatment of dementia-related psychosis. Veterinarian: Adrenaline may further lower blood pressure in animals given this phenothiazine derivative, rather than raise it. Contraindicated in patients with known hypersensitivity to phenothiazine drugs.
Contraindicated in coma or in the presence of large amounts of central nervous system depressants (alcohol, barbiturates, anesthetics, etc.).
For more complete data on drug warnings for prochlorperazine (53 in total), please visit the HSDB record page.

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Pharmacodynamics
Prochlorperazine is an antipsychotic drug whose mechanism of action is to promote postsynaptic inhibition of dopaminergic neurons. It also exerts its antiemetic effect through antidopaminergic action, with efficacy similar to 5-HT3 receptor antagonists and the antiemetic ondansetron, all of which prevent delayed nausea and vomiting. Prochlorperazine has been shown to inhibit histaminergic, cholinergic, and α1-adrenergic receptors. Blockage of α1-adrenergic receptors may lead to sedation, muscle relaxation, and hypotension. It also has an anxiolytic effect. Compared to other phenothiazine derivatives, prochlorperazine has a weaker sedative effect and is less likely to cause hypotension or enhance the effects of central nervous system depressants and anesthetics. In addition to its primary effect on D2 receptors, one study suggests that prochlorperazine may inhibit P2X7 receptors in human macrophages, thereby inhibiting calcium ion influx.

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Prochlorperazine dimaleate is a first-generation phenothiazine antipsychotic and antiemetic [2] - Its mechanism of action involves competitive antagonism of dopamine D2 receptors in the brain, thereby mediating antipsychotic and antiemetic activity (by blocking dopamine receptors in chemoreceptor trigger zones) [2] - It has been approved for the treatment of schizophrenia, schizoaffective disorder, and severe nausea/vomiting (including chemotherapy-induced, postoperative, and vestibular-induced vomiting) [2] - Prochlorperazine dimaleate exhibits anti-inflammatory activity in vitro and in vivo by inhibiting LPS-induced pro-inflammatory cytokine production and iNOS expression. [1]

C20H24CLN3S.C8H8O8

606.09

605.16

C, 55.49; H, 5.32; Cl, 5.85; N, 6.93; O, 21.12; S, 5.29

84-02-6

4917

White to light yellow crystalline powder

524.8ºC at 760 mmHg

228ºC

271.2ºC

3.944

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]

DSKIOWHQLUWFLG-SPIKMXEPSA-N

InChI=1S/C20H24ClN3S.2C4H4O4/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;2*5-3(6)1-2-4(7)8/h2-3,5-8,15H,4,9-14H2,1H3;2*1-2H,(H,5,6)(H,7,8)/b;2*2-1-

(Z)-but-2-enedioic acid;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)

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.)