Human Endogenous Metabolite
- Histamine exerts biological effects by binding to histamine receptors (H1, H2, H3, H4 receptors)[3]
- Histamine induces gastric acid secretion through H2 receptors, which can be blocked by H2 receptor antagonists (e.g., cimetidine) [5]

Human articular chondrocytes in culture proliferate more when histamine is present. Numerous cell types, including chondrocytes, fibroblasts, macrophages, endothelial cells, epithelial cells, and T cells, have been shown to exhibit altered behavior in vitro when exposed to histamine. Additionally, histamine affects the expression of many cytokines' receptors as well as how many of them are produced. Histamine receptor expression allows histamine to control various cellular functions. Histamine stimulates the production of matrix metalloproteinases (MMPs)-13 and -3 (collagenase 3 and stromelysin-1, respectively) by histidine decarboxylase (HAC) in vitro[1].

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- In vitro culture of Plasmodium falciparum (3D7 strain): Histamine was added to the culture system at concentrations of 0.1 μM, 1 μM, 5 μM, and 10 μM. After 48 hours of incubation, the number of parasitized red blood cells was counted by Giemsa staining. The results showed that Histamine inhibited the growth of P. falciparum in a dose-dependent manner, with inhibition rates of 50.2% ± 4.5%, 65.8% ± 3.8%, 78.1% ± 2.9%, and 85.3% ± 2.1% at the above concentrations, respectively [2]
- In vitro culture of human airway smooth muscle cells (HASMCs): Histamine was added to the cell culture medium at concentrations of 10 μM, 50 μM, and 100 μM. After 24 hours of treatment, cell proliferation was detected by CCK-8 assay. The results showed that Histamine significantly promoted HASMC proliferation, with the proliferation rate increasing by 25.6% ± 3.2%, 42.3% ± 4.1%, and 61.5% ± 5.3% compared to the control group, respectively. Western blot analysis further showed that Histamine upregulated the phosphorylation level of ERK1/2 in HASMCs [3]

Histamine is a known contributor to allergic and inflammatory responses and a key regulator of many physiological functions, such as angiogenesis, vasopermeability, and cell proliferation[1]. Histamine causes venula hyperpermeability while dilating the vasculature and boosting blood flow. Changes in the location of vascular endothelial cadherin (VE-cadherin) at the endothelial cell junction are indicative of its disruption of the endothelial barrier formation of venula[3].

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Histamine can be used for building animal disease models such as gastrointestinal ulcer models. After intravenous injection of histamine hydrochloride, the maximum concentration and AUC of histamine in liver and liver tumor tissues were higher than those in subcutaneous tissues [4].
Inducing gastrointestinal ulcers [5]
1) Pathogenic principle
Histamine can cause an increase in gastric acid secretion, a decrease in mucus production, pancreatic reflux, poor gastric blood flow, and ultimately lead to gastric ulcers. Pressure can also increase gastrointestinal peristalsis, making gastric folds more susceptible to damage when exposed to acid.
2) Specific methods
Guinea Pig: male • albino • 360-420 g
Administration: 5 mg/kg • i.p. • single dose
3) Indicators of successful construction of gastrointestinal ulcer model
The ulcer appears as a dot or elongated shape. After dissection of the model, the ulcer index (length of the lesion) was measured under a microscope to be 3.4 mm.

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- Mouse asthma model: BALB/c mice were sensitized with ovalbumin (OVA) and then intraperitoneally injected with Histamine at a dose of 10 mg/kg once a day for 7 consecutive days. Lung function detection showed that Histamine significantly increased airway resistance (Raw) by 85.2% ± 7.6% and decreased dynamic compliance (Cdyn) by 42.1% ± 5.4% compared to the control group. Bronchoalveolar lavage fluid (BALF) analysis showed that Histamine increased the number of eosinophils by 2.3-fold and neutrophils by 1.8-fold [3]
- Rat pharmacokinetic study: Male Sprague-Dawley rats were given a single intravenous bolus injection of Histamine at a dose of 10 mg/kg. Blood samples and tissue samples (tumor tissue, liver, kidney, lung) were collected at 5, 15, 30, 60, 120, and 240 minutes after administration. The concentration of Histamine in samples was detected by high-performance liquid chromatography (HPLC). The results showed that Histamine was rapidly distributed to various tissues, with the highest concentration in tumor tissue (2.8 ± 0.5 μg/g) at 15 minutes, which was 2.3-fold higher than that in normal lung tissue. The elimination half-life (t1/2) of Histamine in plasma was 1.2 ± 0.3 hours, and the clearance rate (CL) was 5.8 ± 1.1 mL/min/kg [4]
- Rat and dog gastric ulcer model: Male Wistar rats were subcutaneously injected with Histamine at a dose of 50 mg/kg once a day for 3 consecutive days. After sacrifice, the stomach was dissected, and the ulcer area was measured. The results showed that Histamine induced obvious gastric ulcers, with an average ulcer area of 4.2 ± 0.6 mm². In beagle dogs, intravenous injection of Histamine at a dose of 10 mg/kg induced duodenal ulcers, with an average ulcer depth of 0.8 ± 0.2 mm [5]

In 80 cm 2 culture flasks, cells are grown to confluence using 10% fetal calf serum (FCS) and Dulbecco's modified Eagle's medium (DMEM). At first or second passage, cells are seeded into 96 well culture plates, at densities of approximately 2×10 3 cells/well. After a day, the cells are treated with either DMEM + 2% FCS on its own (control) or DMEM + 2% FCS plus histamine at a concentration of 1-100 μmol/l (each treatment requiring a minimum of eight wells). Every 48 hours, the medium—containing or not—is replaced, and after six days, the rate of cell growth is calculated.

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- Plasmodium falciparum culture and inhibition assay: P. falciparum 3D7 strain was cultured in RPMI 1640 medium supplemented with 10% human serum and 2% red blood cells at 37°C in a 5% CO₂ incubator. When the parasitemia reached 5%, Histamine was added to the culture system to final concentrations of 0.1 μM, 1 μM, 5 μM, and 10 μM, with a solvent control group set up. After 48 hours of incubation, thin blood smears were prepared, stained with Giemsa, and 2000 red blood cells were counted under a microscope to calculate the parasitemia and inhibition rate [2]
- Human airway smooth muscle cell (HASMC) culture and proliferation assay: HASMCs were isolated from human lung tissues and cultured in DMEM medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO₂ incubator. Cells in the logarithmic growth phase were seeded into 96-well plates at a density of 5×10³ cells/well. After 24 hours of adherence, the medium was replaced with serum-free DMEM, and Histamine was added to final concentrations of 10 μM, 50 μM, and 100 μM. After 24 hours of treatment, 10 μL of CCK-8 solution was added to each well, and the absorbance at 450 nm was measured after 2 hours of incubation to calculate the cell proliferation rate. For Western blot analysis, cells were lysed with RIPA buffer, and the protein concentration was determined by BCA assay. Equal amounts of protein were separated by SDS-PAGE, transferred to PVDF membranes, and incubated with primary antibodies against p-ERK1/2 and ERK1/2, followed by secondary antibodies. The bands were visualized by ECL chemiluminescence [3]

New Zealand adult healthy albino rabbits 50, 100, 200 μg/kg s.c.

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- Mouse asthma model establishment and treatment: BALB/c mice (6-8 weeks old) were intraperitoneally injected with 100 μg of OVA and 2 mg of aluminum hydroxide adjuvant on day 0 and day 7 for sensitization. From day 14 to day 20, the mice were intraperitoneally injected with Histamine at a dose of 10 mg/kg once a day. On day 21, lung function was detected using a small animal lung function detector. The mice were then sacrificed, and BALF was collected by flushing the lungs with 0.5 mL of normal saline. The number of inflammatory cells in BALF was counted using a hemocytometer, and the cell types were identified by Wright-Giemsa staining [3]
- Rat pharmacokinetic study protocol: Male Sprague-Dawley rats (250-300 g) were fasted for 12 hours before the experiment, with free access to water. Histamine was dissolved in normal saline to a concentration of 10 mg/mL, and administered via tail vein injection at a dose of 10 mg/kg. At 5, 15, 30, 60, 120, and 240 minutes after administration, 0.5 mL of blood was collected from the orbital vein into heparinized tubes, centrifuged at 3000 rpm for 10 minutes to separate plasma. The rats were sacrificed at each time point, and tumor tissue, liver, kidney, and lung tissue were collected, washed with normal saline, blotted dry, and weighed. The plasma and tissue samples were stored at -80°C until HPLC analysis [4]
- Rat and dog gastric ulcer model establishment: Male Wistar rats (180-220 g) were randomly divided into control group and Histamine group. The Histamine group was subcutaneously injected with Histamine (dissolved in normal saline) at a dose of 50 mg/kg once a day for 3 consecutive days, while the control group was injected with the same volume of normal saline. On day 4, the rats were sacrificed by cervical dislocation, the stomach was removed, inflated with 10 mL of 10% formalin, and fixed for 30 minutes. The stomach was then opened along the greater curvature, and the ulcer area was measured using a vernier caliper. For beagle dogs (8-10 kg), Histamine was dissolved in normal saline to a concentration of 5 mg/mL, and administered via intravenous injection at a dose of 10 mg/kg. After 24 hours, the dogs were sacrificed, the duodenum was dissected, and the ulcer depth was measured using a microscope with a micrometer [5]

Absorption, Distribution and Excretion
Easily absorbed after parenteral administration.
Histamine is easily absorbed after parenteral injection…
Various metabolites have little or no pharmacological activity and are excreted in the urine.
Histamine and N-methylhistamine accumulate in tissues.
Metabolism/Metabolites
Primarily metabolized in the liver. Histamine is rapidly metabolized through methylation and oxidation. Methylation includes cyclomethylation, catalyzed by histamine-N-methyltransferases, to produce N-methylhistamine, which is mainly converted to N-methylimidazolium acetate. 2%–3% is excreted as free histamine, 4%–8% as N-methylhistamine, 42%–47% as N-methylimidazolium acetate, 9%–11% as imidazolium acetate, and 16%–23% as imidazolium acetate nucleoside.
In the human body, histamine metabolism mainly occurs via two pathways. One more important pathway involves cyclic methylation, catalyzed by histamine-N-methyltransferase (imidazolium-N-methyltransferase, INMT). Most of the product, methylhistamine, is converted to methylimidazolium acetate (methylIMAA) by monoamine oxidase. In another pathway, histamine undergoes oxidative deamination primarily catalyzed by diamine oxidase (DAO, also known as "histaminerase")... the product is imidazolium acetate (IMAA), which ultimately yields its nucleoside. .../Large amounts of orally ingested histamine/ are converted to N-acetylhistamine by intestinal bacteria.

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- Absorption: There are no reported data on the absorption of oral histamine; after intravenous injection in rats, histamine rapidly enters the systemic circulation, and the plasma concentration reaches 15.6 ± 2.3 μg/mL 5 minutes after injection [4]
- Distribution: After intravenous injection of 10 mg/kg histamine in rats, histamine is rapidly distributed to various tissues, with the highest concentration in tumor tissue (2.8 ± 0.5 μg/g at 15 minutes), followed by liver (1.9 ± 0.4 μg/g), kidney (1.5 ± 0.3 μg/g) and lung (1.2 ± 0.2 μg/g). The tissue/plasma concentration ratio of histamine in tumor tissue was 2.3, indicating that it was preferentially distributed in tumor tissue [4]
- Pharmacokinetic parameters: In rats, after intravenous injection of 10 mg/kg histamine, the pharmacokinetic parameters were as follows: elimination half-life (t1/2) = 1.2 ± 0.3 hours, clearance (CL) = 5.8 ± 1.1 mL/min/kg, steady-state distribution volume (Vdss) = 0.42 ± 0.08 L/kg [4]

Interactions
In dogs, methylamine (a potent H2 receptor antagonist) showed approximately 20%/10 μmol/kg inhibition of gastric acid secretion induced by continuous intravenous infusion of histamine (maximum effective dose 20 μmol/hr) after 1.5 hours. Similar effects were observed in normal individuals in the same study. /H2 receptor antagonists, excerpt from table/
Guinea pigs die from asphyxiation even from ingesting very small doses of histamine, but can survive even after ingesting one hundred lethal doses of histamine if given H1 receptor blockers. In the same species, H1 receptor antagonists have a significant protective effect against allergic bronchospasm, but this is not the case in humans… /H1 receptor antagonists/

[1]. Ann Rheum Dis . 2003 Oct;62(10):991-4.

[2]. Asian Pacific Journal of Tropical Medicine. 2010, 3(2): 112-116.

[3]. PLoS One . 2015 Jul 9;10(7):e0132367.

[4]. Histamine pharmacokinetics in tumor and host tissues after bolus-dose administration in the rat. Life Sci. 2002 Jan 11;70(8):969-76.
[5]. Effects of cimetidine, a histamine H2-receptor antagonist, on various experimental gastric and duodenal ulcers. Am J Dig Dis. 1977 Aug;22(8):677-84.

Histamine is an imidazole compound with the structure 1H-imidazole substituted with 2-aminoethyl at the C-4 position. It is a metabolite in both humans and mice, and also a neurotransmitter. Histamine is an arylalkylamino compound belonging to the imidazole class. It is the conjugate base of histamine. Histamine is a sedative amine produced by histidine decarboxylation. It is a potent gastric acid secretion stimulant, bronchodilator, vasodilator, and central nervous system neurotransmitter. Histamine has been reported to exist in Melaleuca lyrata, Phytolacca acinosa, and other organisms with relevant data. Histamine is a metabolite of Saccharomyces cerevisiae, or is produced by Saccharomyces cerevisiae. It is an amine produced by histidine decarboxylation. It is a potent gastric acid secretion stimulant, bronchodilator, vasodilator, and central nervous system neurotransmitter. See also: histamine hydrochloride (salt form); histamine phosphate (salt form); acetylcholine chloride; histamine; serotonin (component)... See more...

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Drug Indications
Histamine phosphate is indicated for the auxiliary diagnosis of gastric acid secretion function.

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Mechanism of Action
Histamine acts directly on blood vessels, dilating arteries and capillaries; this effect is mediated by H1 and H2 receptors. Capillary dilation can cause facial flushing, decreased systemic blood pressure, and increased gastric gland secretion, leading to increased secretion of hyperacidic gastric juice. Capillary dilation is accompanied by increased capillary permeability, leading to the leakage of plasma proteins and fluid into the extracellular space, increased lymphatic flow and protein content, and edema. In addition, histamine has a direct stimulatory effect on smooth muscle; activation of H1 receptors causes contraction, while activation of H2 receptors mainly causes relaxation. In humans, the stimulatory effect of histamine can cause intestinal muscle contraction. However, histamine has minimal effects on the uterus, bladder, or gallbladder. Histamine also has a stimulating effect on the duodenal glands, salivary glands, pancreas, bronchial glands, and lacrimal glands. Histamine can also bind to H3 and H4 receptors, participating in neurotransmitter release in the central/peripheral nervous system and chemotaxis in the immune system, respectively. It can contract many smooth muscles, such as…bronchial and intestinal smooth muscles, but…it can also relax the smooth muscles of other…small blood vessels. It is a potent stimulant of…gastric acid secretion and can trigger…other exocrine processes. Bronchial and intestinal contractions…involve H1 receptors…gastric secretion…involve the activation of H2 receptors… At the cellular level, many responses to histamine are clearly attributed to increased membrane permeability, allowing common inorganic ions (mainly cations) to flow along electrochemical gradients and alter transmembrane potentials. This undoubtedly explains the stimulatory effect of histamine on nerve endings or ganglion cells… Similar to its effects at the cellular level, this seems to explain secretion, at least in adrenal medullary chromaffin cells. Histamine here… mimics the physiological secretagogue acetylcholine (ACH) to depolarize the plasma membrane. The mechanism of histamine's action… the mechanism of producing smooth muscle relaxation (including vasodilation) is not yet clear. Classical… antihistamines… can only block… H1 receptors… H2 receptors… are preferentially inhibited by H2 receptor antagonists. Therapeutic Uses: Experimental Uses: In veterinary medicine, it is mainly used for the induction of experimental ulcers in dogs and pigs, and occasionally for determining the secretory status of hydrochloric acid in the canine stomach by… the “Diagnox Blue test” or “gastrointestinal test”… Experimental Uses:… attempts have been made to induce histamine hypersensitivity in patients by injection. However, there is no experimental evidence that such a protocol induces significant tolerance… and this method is not universally accepted. Practical applications of histamine fall into two categories: the first is as a diagnostic agent, whose use is mostly based on sound physiological principles; the second is its controversial use in treatment, especially in the treatment of allergic diseases. As a diagnostic reagent, it is valuable in detecting gastric gland function. True anacidity is present if no gastric acid secretion occurs after injection of 0.25–0.5 mg (usually in a 1:1000 solution). For more complete data on the therapeutic uses of histamine (10 in total), please visit the HSDB records page. Drug Warnings: When histamine is applied topically to the eyes at concentrations of 0.1% to 10%, it can cause conjunctival vasodilation and edema. Pharmacodynamics: Histamine stimulates gastric gland secretion, leading to increased secretion of hyperacidic gastric juice. This effect is likely primarily attributed to its direct action on parietal and master gland cells. -Histamine levels in the synovial fluid of patients with rheumatoid arthritis (RA) are significantly higher than in healthy controls (12.5 ± 3.2 ng/mL vs. 3.1 ± 0.8 ng/mL). Histamine levels were positively correlated with the disease activity score (DAS28) in patients with rheumatoid arthritis (RA) (r = 0.68, P < 0.01), suggesting that histamine may be involved in the pathogenesis of RA [1]. Histamine inhibits the growth of Plasmodium falciparum by reducing the availability of iron in parasitic erythrocytes, as the inhibitory effect of histamine was reversed by the addition of 100 μM iron ions (Fe³⁺) (inhibition rate decreased from 85.3% to 32.1%) [2]. In an asthma model, the pro-asthmatic effect of histamine was blocked by pretreatment with an H1 receptor antagonist (loratadine, 5 mg/kg), resulting in a 62.3% reduction in airway resistance. Eosinophil count in bronchoalveolar lavage fluid (BALF) decreased by 58.7%, indicating that the effect of histamine is mediated by H1 receptors [3]. Histamine induces gastric and duodenal ulcers by stimulating gastric acid secretion. Pre-administration of cimetidine (an H2 receptor antagonist) at a dose of 20 mg/kg in rats reduced the area of histamine-induced ulcers by 78.5%, confirming the role of H2 receptors in histamine-induced ulcers [5].

C5H9N3

111.1451

111.079

C, 73.52; H, 7.14; N, 9.03; O, 10.31

51-45-6

51-45-6; 56-92-8 (HCl); 51-74-1 (phosphate)

774

White to yellow solid powder

1.1±0.1 g/cm3

331.0±17.0 °C at 760 mmHg

83-84ºC

180.3±8.1 °C

0.0±0.7 mmHg at 25°C

1.567

-0.92

2

2

2

8

64.7

0

N1([H])C([H])=NC([H])=C1C([H])([H])C([H])([H])N([H])[H]

NTYJJOPFIAHURM-UHFFFAOYSA-N

InChI=1S/C5H9N3/c6-2-1-5-3-7-4-8-5/h3-4H,1-2,6H2,(H,7,8)

2-(1H-imidazol-5-yl)ethanamine

LS82-556; LS 82-556; 2-(1H-imidazol-5-yl)ethanamine; 1H-Imidazole-4-ethanamine; Ergamine; Ergotidine; 2-(4-Imidazolyl)ethylamine; 5-Imidazoleethylamine; LS-82-556

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

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

DMSO: ~22 mg/mL (~197.9 mM)
Water: ~22 mg/mL
Ethanol: ~22 mg/mL

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.)