Histamine receptor

Cetirizine (>5 μM) at higher doses inhibits the release of GM-CSF and IL-8 from A549 cells treated with IL-1β. Cetirizine has anti-inflammatory properties in addition to acting as a histamine H1 receptor antagonist[2].

When mice are exposed with ragweed pollen and immunized, cetirizine (20 mg/kg, mice) inhibits the production of IL-8 and MIF, hence reducing inflammation[3].

Recent studies suggest that several second-generation antihistamines can modulate various inflammatory reactions besides their H(1)-receptor antagonism. The antihistamine cetirizine is a racemic mixture of levocetirizine and dextrocetirizine. The aim of this study was to investigate the effects of these two antihistamines (cetirizine and levocetirizine) on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-8 secretion in A549 human airway epithelial cells. A549 cells were preincubated with cetirizine (0.1, 1, 2.5, 5, and 10 microM) or levocetirizine (0.1, 1, 2.5, 5, and 10 microM) individually for 16 hours and were then stimulated with IL-1beta for 8 hours. The levels of GM-CSF and IL-8 in cultured supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Our data showed that cetirizine (5 and 10 microM) and levocetirizine (2.5, 5, and 10 microM) significantly suppressed GM-CSF secretion from A549 cells stimulated with IL-1beta (p<0.05). Cetirizine (10 microM) and levocetirizine (5 and 10 microM) significantly suppressed IL-8 secretion after A549 was stimulated. The suppressive effect was comparable between levocetirizine, 2.5 microM, and cetirizine, 5 microM, as well as levocetirizine, 5 microM, and cetirizine, 10 microM. Moreover, levocetirizine, 5 microM, was better than cetirizine, 5 microM, on suppressing IL-8 secretion, but such a difference did not appear in other conditions. Our results suggest that cetirizine and levocetirizine at higher concentrations can reduce the release of GM-CSF and IL-8 from A549 cells stimulated with IL-1beta. These observations indicate that the two second-generation antihistamines may exert anti-inflammatory effects beyond histamine H(1)-receptor antagonist, and levocetirizine plays a major role in terms of this activity[2].

Cell Viability Assay[2]
Cell Types: Human airway epithelial cell line A549.
Tested Concentrations: 0-10 μM.
Incubation Duration: 24 h.
Experimental Results: The survival of A549 cells incubated with various concentrations of cetirizine (0.1, 1, 2.5, 5, and 10 μM ) for 24 hrs (hours) were all higher than 90% when comparing with the control group by MTT test. Cetirizine, 5 and 10 μM, suppressed GM-CSF release by 70.71 and 61.55%, respectively. Preincubation with cetirizine, 10 μM, suppressed the IL -8 secretion by 75.04%.

Animal/Disease Models: Male 8weeks old BALB/ c mice (25-30 g) immunized and challenged with ragweed pollen[3].
Doses: 2 or 20 mg/kg.
Route of Administration: Orally, diluted in sterile water on days 18, 19, and 20.
Experimental Results: The neutrophilia at 8 h and eosinophilia at 24 h induced by ragweed pollen extract per os were Dramatically decreased in the mice treated with 20 mg/kg. The dosage with 2 mg/kg had no effect.

Absorption, Distribution and Excretion
In adult volunteers, cetirizine is rapidly absorbed after oral administration of tablets or syrup, with a time to peak concentration (Tmax) of approximately 1 hour. Bioavailability is similar in tablet and syrup formulations. When healthy subjects took multiple doses of cetirizine (10 mg tablets once daily) for 10 consecutive days, the mean peak plasma concentration (Cmax) was 311 ng/mL. Effect of Food on Absorption Food had no effect on the AUC of cetirizine, but Tmax was delayed by 1.7 hours and Cmax decreased by 23% in the food-treated state. Primarily excreted in the urine. After oral administration, 70%–85% of the drug is excreted in the urine and 10%–13% in the feces. Apparent volume of distribution: 0.44 ± 0.19 L/kg. Apparent systemic clearance: Approximately 53 mL/min. Cetirizine is primarily excreted by the kidneys. Dosage adjustments are required for patients with moderate to severe renal impairment and those undergoing hemodialysis. A quality balance study in six healthy male volunteers showed that 70% of the administered radioactive material was excreted in urine and 10% in feces. Approximately 50% of the radioactive material in urine is present unchanged. The rapid increase in peak plasma radioactivity is primarily related to the unchanged drug, suggesting a low degree of first-pass metabolism. Cetirizine is metabolized via oxidative dealkylation to a metabolite with negligible antihistamine activity. The enzyme responsible for this metabolism has not been identified. The mean plasma protein binding of cetirizine is 93%, concentration-independent within the range of 25–1000 ng/mL (including observed therapeutic plasma concentrations). Cetirizine is rapidly absorbed in adults after oral administration of tablets, chewable tablets, or syrup, with a time to peak concentration (Tmax) of approximately 1 hour. Bioavailability is comparable between tablet and syrup formulations. The bioavailability of Zyrtec tablets and Zyrtec chewable tablets (whether taken with or without water) is also comparable. Following multiple doses of cetirizine (10 mg once daily for 10 consecutive days) in healthy volunteers, a mean peak plasma concentration (Cmax) of 311 ng/mL was observed. No drug accumulation was observed. The pharmacokinetics of cetirizine were linear across oral doses ranging from 5 to 60 mg. Food had no effect on the exposure (AUC) of cetirizine tablets or chewable tablets, but delayed the time to peak concentration (Tmax) by 1.7 hours and 2.8 hours, respectively, and reduced the peak plasma concentration (Cmax) by 23% and 37%, respectively. In children aged 7 to 12 years, a single oral dose of 5 mg cetirizine capsules resulted in a mean peak plasma concentration of 275 ng/mL. Based on interstudy comparisons, the weight-normalized apparent systemic clearance in this pediatric population was 33% higher than in adults, and the elimination half-life was 33% shorter. In children aged 2 to 5 years, a 5 mg dose of cetirizine resulted in a mean peak plasma concentration of 660 ng/mL. Based on cross-study comparisons, the weight-normalized apparent total clearance in this pediatric population was 81% to 111% higher and the elimination half-life was shortened by 33% to 41% compared to adults. In pediatric patients aged 6 to 23 months who received a single dose of 0.25 mg/kg cetirizine oral solution (mean dose 2.3 mg), the mean Cmax was 390 ng/mL. Based on cross-study comparisons, the weight-normalized apparent total clearance in this pediatric population was 304% higher and the elimination half-life was shortened by 63% compared to adults. The mean AUC(0-t) of children aged 6 months to 2 years after receiving the maximum dose of cetirizine solution (2.5 mg twice daily) was expected to be twice that of adults receiving 10 mg cetirizine tablets once daily. For more complete data on absorption, distribution, and excretion of cetirizine (7 types), please visit the HSDB records page.

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Metabolism/Metabolites
A quality balance clinical trial involving six healthy male volunteers showed that after administration of cetirizine, 70% of the radioactive material was detected in urine and 10% in feces. Approximately 50% of the radioactive material was detected in urine as unchanged cetirizine. The rapid increase in plasma radioactivity peak was primarily related to the parent drug, indicating a low level of first-pass metabolism. This may prevent potential interactions between cetirizine and drugs acting on hepatic cytochrome enzymes. Cetirizine is partially metabolized via oxidative O-dealkylation to a metabolite with weak antihistamine activity. The enzyme responsible for this step of cetirizine metabolism has not been identified. A quality balance study in six healthy male volunteers showed that 70% of the administered radioactive material was recovered in urine and 10% in feces. Approximately 50% of the radioactive material in urine was present as the parent drug. The rapid increase in plasma radioactivity peak was primarily related to the parent drug, indicating a low degree of first-pass metabolism. Cetirizine is metabolized to a metabolite with negligible antihistamine activity via oxidative O-dealkylation, but the extent of this metabolism is limited. The enzyme responsible for this metabolism has not been identified. Pharmacokinetic parameters of hydroxyzine and its active metabolite cetirizine were determined in six healthy dogs after oral and intravenous administration of 2 mg/kg hydroxyzine. Plasma drug concentrations were determined using high-performance liquid chromatography (HPLC). Pharmacodynamic studies evaluated the inhibitory effects of hydroxyzine on histamine and anti-canine IgE-mediated skin wheal formation. Pharmacokinetic and pharmacodynamic correlations were determined using computer modeling. The mean systemic bioavailability of orally administered hydroxyzine was 72%. Hydroxyzine is rapidly converted to cetirizine regardless of the route of administration. The mean area under the curve (AUC) of cetirizine after intravenous and oral administration was 8 and 10 times that of hydroxyzine, respectively. After oral administration of hydroxyzine, the mean peak concentration of cetirizine was approximately 2.2 μg/mL, and the mean peak concentration of hydroxyzine was approximately 0.16 μg/mL. Following intravenous and oral administration of hydroxyzine, the terminal half-life of cetirizine ranged from 10 to 11 hours. The relationship between cetirizine plasma concentration and wheal inhibition rate exhibited an S-shaped curve. Maximum inhibition rates (82% for histamine-mediated skin response and 69% for anti-canine IgE-mediated skin response) were observed within the first 8 hours after administration, correlated with cetirizine plasma concentrations above 1.5 μg/mL. Pharmacological models indicated that increasing the dose or frequency of hydroxyzine did not significantly inhibit histamine responses more effectively than twice-daily administration of 2 mg/kg hydroxyzine. In summary, hydroxyzine rapidly converts to cetirizine. The reduction in wheal formation was almost entirely attributable to cetirizine. Pharmacodynamic models predicted that twice-daily oral administration of 2 mg/kg hydroxyzine would achieve the maximum antihistamine effect.
Half-life: 8.3 hours

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Biological half-life
The plasma elimination half-life is 8.3 hours. In multiple pharmacokinetic studies, the mean elimination half-life in 146 healthy volunteers was 8.3 hours… This study investigated the pharmacokinetics of cetirizine, a second-generation H1 receptor antagonist, in 15 infants (mean age ± standard deviation: 12.3 ± 5.4 months) who received a single dose of 0.25 mg/kg cetirizine solution. The elimination half-life was 3.1 ± 1.8 hours…

Toxicity Summary
Cetirizine competes with histamine for H1 receptor sites on the effector cell surface, thereby inhibiting histamine-induced edema, erythema, and pruritus. The low incidence of sedation can be attributed to the reduced penetration of cetirizine into the central nervous system due to the less lipophilic carboxyl group on the ethylamine side chain. Interactions
A 72-year-old woman with renal insufficiency experienced syncope after 3 days of oral picicacarb (150 mg/day) followed by 3 days of oral cetirizine (20 mg/day). Examination revealed widened QRS complexes and bradycardia. Her symptoms subsided upon discontinuation of picicacarb. Plasma concentrations were significantly elevated during the combined use of both drugs; however, cetirizine concentrations decreased after discontinuation of picicacarb, despite continued cetirizine treatment, suggesting that the syncope was caused by a drug interaction. A pharmacokinetic study in six healthy male volunteers found that single doses of cetirizine (20 mg) or pizzicabine (50 mg), or a combination of both, significantly reduced renal clearance of both drugs (picicabine from 475 ± 101 mL/min to 279 ± 117 mL/min, and cetirizine from 189 ± 37 mL/min to 118 ± 28 mL/min; P values were 0.008 and 0.009, respectively). In vitro studies using Xenopus oocytes microinjected with human organic cation transporter 2 (HCG 2) and renal cells transfected with human multidrug resistance protein 1 (MDT 1) showed that both cetirizine and pizzicabine inhibited the transport of substrates of these transporters. Therefore, the elevated drug concentrations in renal tubular cells may be due to pharmacokinetic drug interactions mediated by MDT 1 or HCG 2 (or both), leading to the arrhythmia in our patient. Although cetirizine is less likely to cause arrhythmias than other histamine H1 receptor blockers, this interaction should still be considered, especially in patients with renal insufficiency taking picicacarb. This article reports a case of an 88-year-old male patient who experienced enhanced anticoagulant activity after concurrent use of cetirizine and acenitroprusside. The patient had been treated with acenitroprusside (1 mg/day) for one year for deep vein thrombosis. Three laboratory tests performed 8 weeks prior to admission showed prothrombin levels of 58%, 59%, and 59%, with an international normalized ratio (INR) of 1.5. The patient presented to the emergency department with severe epistaxis after an accidental fall, which did not respond to conventional treatment. Laboratory tests showed a serum total protein level of 7.5 g/dL, serum creatinine of 1.4 mg/dL, and a platelet count of 564 × 10³/mm³; prothrombin levels were below 10%, and the INR was above 14. Three days prior to admission, the patient had started taking cetirizine (10 mg/day) for allergic rhinitis. Upon admission, cetirizine was discontinued, and the patient was given coagulation factor IX complex therapy. After treatment, prothrombin levels returned to 100%. The patient was discharged one week later with an INR of 1.42. This study investigated the pharmacokinetics of the histamine H(1) receptor antagonist cetirizine in horses, and the effect of prior administration of the antiparasitic macrolide ivermectin on cetirizine pharmacokinetics. Following oral administration of 0.2 mg/kg body weight of cetirizine to horses, the mean terminal half-life was 3.4 hours (range 2.9–3.7 hours), and the maximum plasma concentration was 132 ng/mL (101–196 ng/mL). The time to reach maximum plasma concentration was 0.7 hours (0.5–0.8 hours). Oral administration of 0.2 mg/kg body weight of ivermectin 1.5 hours prior to cetirizine administration had no effect on its pharmacokinetics. However, pretreatment with ivermectin 12 hours prior to cetirizine administration increased the area under the plasma concentration-time curve by 60%. The maximum plasma concentration, terminal half-life, and mean residence time were also significantly increased after 12-hour pretreatment. Ivermectin is an inhibitor of P-glycoprotein, a major drug efflux transporter at various sites on the cell membrane. The increased plasma concentration of cetirizine after ivermectin pretreatment is likely primarily attributable to the inhibition of P-glycoprotein in proximal renal tubular cells, leading to reduced renal secretion.

[1]. Cetirizine. Drugs 46 (6): 1055•1080, 1993.

[2]. Influence of cetirizine and levocetirizine on two cytokines secretion in human airway epithelial cells. Allergy Asthma Proc. 2008 Sep-Oct;29(5):480-5.

[3]. Cetirizine, an H1-receptor antagonist, suppresses the expression of macrophage migration inhibitory factor: its potential anti-inflammatory action. Clin Exp Allergy. 2004 Jan;34(1):103-9.

Therapeutic Uses

Cetirizine, alone or in fixed-dose combination with pseudoephedrine hydrochloride, is used for self-medication to relieve symptoms of seasonal allergic rhinitis (e.g., hay fever) or other upper respiratory tract allergies. Cetirizine, alone or in fixed-dose combination with pseudoephedrine hydrochloride, is also used to treat symptoms of perennial allergic rhinitis. Fixed-dose combination is recommended only when the combined antihistamine and nasal decongestant effects of the combination are needed. /US Product Label/
Cetirizine is used for self-medication to relieve itching symptoms caused by chronic idiopathic urticaria (e.g., rubella). /US Product Label/
Medication (Veterinary): The efficacy of antihistamines in treating itching varies greatly. The most commonly used antihistamines include… cetirizine hydrochloride…. /Cetirizine Hydrochloride/

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Drug Warning
In a 1-week controlled study of patients aged 6–11 months, children taking cetirizine showed significantly more irritability/irritability than those taking a placebo. In another controlled study of patients 12 months and older, the incidence of insomnia was higher in children taking cetirizine than in those taking a placebo (9% vs. 5.3%, respectively).
In patients taking 5 mg or more daily, the incidence of fatigue was 3.6% in those taking cetirizine and 1.3% in those taking a placebo; the incidence of discomfort was 3.5% in those taking a placebo and 1.8% in those taking a placebo.
In patients aged 12 years and older taking cetirizine, the incidence of fatigue and dizziness was 5.9% and 2%, respectively, compared to 2.6% and 1.2% in those taking a placebo. In patients aged 12 years and older taking this drug, more than 2% reported headaches; however, the incidence of headaches was higher in patients taking a placebo. In clinical trials in patients aged 6–11 years, the incidence of headaches was 11%, 14%, and 12.3% in patients taking 5 mg, 10 mg, or a placebo, respectively. Less than 2% of patients aged 12 years and older and children aged 6–11 years taking cetirizine hydrochloride have reported the following adverse reactions: incoordination, ataxia, confusion, thought disorder, agitation, amnesia, anxiety, depersonalization, depression, mood instability, euphoria, inattention, insomnia, sleep disturbances, tension, auditory hallucinations, dysarthria, weakness, malaise, pain, hyperesthesia, hypoesthesia, hyperkinesis, hypertonia, migraine, myelitis, paralysis, paresthesia, ptosis, syncope, tremor, convulsions, and dizziness; however, a causal relationship between these adverse reactions and the drug has not been established. During post-marketing surveillance, reports of aggressive reactions, seizures, hallucinations, suicidal ideation, and suicide were rare. In patients aged 12 years and older, the most common adverse reaction during cetirizine treatment was somnolence, occurring in 11%, 14%, and 6% of patients receiving 5 mg, 10 mg, or placebo, respectively. Overall, the incidence of somnolence was 13.7% and 6.3% in patients receiving cetirizine and placebo, respectively. Furthermore, in clinical trials in patients aged 6–11 years, the incidence of somnolence was 1.9%, 4.2%, and 1.3% in patients receiving 5 mg, 10 mg, or placebo, respectively. It has been reported that 1% and 0.6% of patients receiving cetirizine and placebo, respectively, discontinued treatment due to somnolence. In patients aged 6–24 months, the frequency of somnolence was substantially the same in patients receiving cetirizine and those receiving placebo.
In patients aged 12 years and older with seasonal allergic rhinitis, adverse reactions reported in 1% or more of patients taking cetirizine hydrochloride and pseudoephedrine hydrochloride fixed-release tablets (Zyrtec-D) included insomnia, dry mouth, fatigue, somnolence, pharyngitis, epistaxis, accidental injury, dizziness, and sinusitis.
For more complete data on drug warnings for cetirizine (31 total), please visit the HSDB record page.

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Pharmacodynamics
Systemic and Respiratory Effects Cetirizine, the active metabolite of the piperazine H1 receptor antagonist hydroxyzine, is used to relieve or eliminate symptoms of chronic idiopathic urticaria, perennial allergic rhinitis, seasonal allergic rhinitis, allergic asthma, physical urticaria, and atopic dermatitis. The clinical efficacy of cetirizine in treating allergic respiratory disorders has been well-established in numerous trials. Effects on Urticaria/Anti-inflammatory Effects Cetirizine has anti-inflammatory properties and may play a role in the treatment of asthma. There is evidence that cetirizine can improve urticaria symptoms. After a single oral dose, significant suppression of wheals and erythema reactions is observed within 20 minutes in infants, children, and adults, and this suppression can last for 24 hours. Concomitant use of cetirizine can reduce the duration and dosage of topical anti-inflammatory agents used to treat atopic dermatitis.

C21H25CLN2O3

388.888

388.155

C, 64.86; H, 6.48; Cl, 9.12; N, 7.20; O, 12.34

83881-51-0

Cetirizine dihydrochloride;83881-52-1;Cetirizine-d4;1219803-84-5;Cetirizine-d8;774596-22-4;Levocetirizine;130018-77-8;Levocetirizine dihydrochloride;130018-87-0;Cetirizine methyl ester;83881-46-3;Cetirizine-d4 dihydrochloride;Cetirizine-d8 dihydrochloride;2070015-04-0

2678

Crystals from ethanol

1.2±0.1 g/cm3

542.1±45.0 °C at 760 mmHg

110-115°C

281.6±28.7 °C

0.0±1.5 mmHg at 25°C

1.589

2.16

1

5

8

27

443

0

O=C(COCCN1CCN(C(C2C=CC(Cl)=CC=2)C2C=CC=CC=2)CC1)O

ZKLPARSLTMPFCP-UHFFFAOYSA-N

InChI=1S/C21H25ClN2O3/c22-19-8-6-18(7-9-19)21(17-4-2-1-3-5-17)24-12-10-23(11-13-24)14-15-27-16-20(25)26/h1-9,21H,10-16H2,(H,25,26)

Acetic acid, (2-(4-((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)-

Cetirizina; Cetryn; AC170; AC 170 AC-170; Ziptek; Setir; Virlix; Cetirizinum

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)

DMSO : ~250 mg/mL (~642.86 mM)

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.)