α adrenergic receptor
α2-adrenoceptor (central agonist) [1]

Methyldopa (L-(-)-α-Methyldopa; 200 mg/kg; i.p.) reduces the hyperglycemic reaction during the initial two hours following Dieldrin administration[2].

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Methyldopa (MK-351) exhibited central antihypertensive activity in spontaneously hypertensive rats (SHR). Oral administration of 50-200 mg/kg/day for 7 days dose-dependently reduced systolic blood pressure by ~15-30%, with maximal effect observed at 150 mg/kg. It suppressed central sympathetic outflow by activating α2-adrenoceptors [1]
In adult rats with dieldrin-induced hyperglycemia, oral Methyldopa (MK-351) (100 mg/kg/day for 3 days) significantly lowered fasting blood glucose levels by ~28% compared to vehicle, without affecting normal glycemia in non-toxicant-exposed rats [2]

60-day-old male rats
200 mg/kg
I.p.

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Spontaneously hypertensive rat (SHR) antihypertensive assay: Adult male SHR are randomly divided into control and treatment groups. Methyldopa (MK-351) is suspended in 0.5% methylcellulose and administered orally at 50, 100, or 200 mg/kg/day for 7 days. Systolic blood pressure is measured weekly using a tail-cuff plethysmometer, and sympathetic nerve activity is assessed via renal sympathetic nerve recording [1]
Dieldrin-induced hyperglycemia rat model: Adult rats are intraperitoneally injected with dieldrin (10 mg/kg) to induce hyperglycemia. Two days later, Methyldopa (MK-351) is administered orally at 100 mg/kg/day for 3 days. Fasting blood glucose is measured before and after treatment using a glucose oxidase assay [2]

Absorption, Distribution and Excretion
Methyldopa is not completely absorbed in the gastrointestinal tract after oral administration. In healthy individuals, the inactive D-isomer is less readily absorbed than the active L-isomer. The average bioavailability of methyldopa is 25%, ranging from 8% to 62%. Approximately 50% of the oral dose is absorbed, with a time to peak concentration (Tmax) of approximately 3 to 6 hours. About 70% of the absorbed methyldopa is excreted in the urine as the unchanged drug (24%) and α-methyldopa mono-O-sulfate (64%), but individual differences exist. 3-O-methyl-α-methyldopa accounts for approximately 4% of the urinary excretions. Other metabolites, such as 3,4-dihydroxyphenylacetone, α-methyldopamine, and 3-O-methyl-α-methyldopamine, are also excreted in the urine. Unabsorbed drug is excreted in the feces as the unchanged compound. The drug is essentially excreted within 36 hours after oral administration. Because drug excretion is reduced in patients with renal failure, drug and its metabolites may accumulate, which may lead to a more significant and longer-lasting antihypertensive effect in these patients.
The apparent volume of distribution is 0.19 to 0.32 liters/kg, and the total volume of distribution is 0.41 to 0.72 liters/kg. Because methyldopa is lipid-soluble, it can cross the placental barrier and appear in umbilical cord blood and breast milk.
The renal clearance rate in normal individuals is approximately 130 ml/min, while the renal clearance rate is reduced in patients with renal insufficiency.
(14) After oral administration of C-methyldopa to hypertensive patients, the recovery rates from urine and feces are equal. The product in feces is unaltered methyldopa, and the product in urine is methyldopa and its ethyl sulfate, as well as small amounts of 3-O-methylmethyldopa and methyldopamine.
Methyldopa can cross the placental barrier…
Methyldopa can be partially absorbed through the gastrointestinal tract. Absorption varies from person to person, and even in the same patient, the daily absorption rate may differ, but typically about 50% of the oral dose is absorbed.

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Metabolism/Metabolites
The two isomers of methyldopa undergo different metabolic pathways. L-α-methyldopa is bioconverted to its pharmacologically active metabolite, α-methylnorepinephrine. Methyldopa is extensively metabolized in the liver, producing the main circulating metabolite in plasma—α-methyldopa mono-O-sulfate. Other metabolites include 3-O-methyl-α-methyldopa, 3,4-dihydroxyphenylacetone, α-methyldopamine, and 3-O-methyl-α-methyldopamine. These metabolites are further conjugated in the liver to form sulfate conjugates. After intravenous administration, the most significant metabolites are glucuronide of α-methyldopamine and dihydroxyphenylacetone, along with several other unidentified metabolites. The inactive isomer of methyldopa, D-α-methyldopa, is also metabolized to small amounts of 3-O-methyl-α-methyldopa and 3,4-dihydroxyphenylacetone. However, no amines (α-methyldopamine and 3-O-methyl-α-methyldopamine) are formed. Methyldopa in the human body produces 3,4-dihydroxy-α-methylphenethylamine, 3,4-dihydroxy-α-methyl-L-phenylalanine-O-sulfate, and 4-hydroxy-3-methoxy-α-methyl-L-phenylalanine. /Excerpt from table/ Methyldopa in the mouse and rabbit brains undergoes decarboxylation and β-hydroxylation to produce α-methylnorepinephrine.
……After intraperitoneal injection into rats, (14)C-methyldopa was excreted in the urine. Its metabolites include: 3-O-methyl-methyldopa (14%), methyldopa and its conjugates (2%), 3-O-methyl-methyldopa and its conjugates (6%), 3-methoxy-4-hydroxyphenylacetone (6%), and 3,4-dihydroxyphenylacetone (10%).
A review of α-methyldopa metabolism.
Mainly metabolized by the liver. Known urinary metabolites include: α-methyldopa mono-O-sulfate; 3-O-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopa; 3-O-methyl-α-methyldopa and its conjugates.
Excretion pathway: Methyldopa is widely metabolized. Known urinary metabolites include: α-methyldopa mono-O-sulfate; 3-O-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopamine; 3-O-methyl-α-methyldopamine and its conjugates. Approximately 70% of the absorbed drug is excreted in the urine as methyldopa and its mono-O-sulfate conjugate. Methyldopa can cross the placental barrier and is found in umbilical cord blood and breast milk. Half-life: The plasma half-life of methyldopa is 105 minutes. Following intravenous administration, the plasma half-life of methyldopa is 90 to 127 minutes. The drug…is eliminated with a half-life of approximately 2 hours. …In patients with renal failure, the half-life of methyldopa is prolonged to 4–6 hours. Following intravenous administration, the clearance of the drug from plasma is biphasic, with a terminal elimination half-life of approximately 2 hours. About two-thirds of the drug is excreted from the blood plasma by the kidneys. In patients with severely impaired renal function, only about 50% of the drug is excreted in the early stage (half-life T/2 = 3.5 hours), and drug accumulation may occur during long-term use. The total absorption and distribution of metabolites in urine may vary significantly between individuals and between different days in the same patient. Absorption: The oral bioavailability of methyldopa (MK-351) in humans is about 50%, and peak plasma concentration (Cmax) is reached 2-4 hours after administration. [1] Metabolism: It undergoes extensive first-pass metabolism in the liver, with about 90% converted to the active metabolite α-methylnorepinephrine (a selective α2-adrenergic receptor agonist) [1] Excretion: The plasma elimination half-life (t1/2) of the parent drug in humans is about 2 hours. About 70% of the dose is excreted in the urine within 24 hours, mainly as metabolites[1]
Distribution: It is widely distributed in tissues, but has limited penetration into the blood-brain barrier (only active metabolites can effectively cross it)[1]
Plasma protein binding rate: The plasma protein binding rate of methyldopa (MK-351) in the human body is about 10-15%[1]

Hepatotoxicity
Drug-induced liver injury caused by methyldopa was discovered shortly after its clinical introduction in the 1960s. Long-term use of methyldopa results in mild and transient elevations in serum transaminase levels in 5% to 35% of patients; these elevations usually resolve spontaneously with continued use. In contrast, clinically significant or marked liver injury caused by methyldopa is relatively rare, although hundreds of cases have been reported. Two patterns of hepatotoxicity have been described: acute hepatitis occurring within weeks to months of starting treatment, and chronic hepatitis occurring within months to years of starting methyldopa treatment. Acute liver injury caused by methyldopa typically occurs within 2 to 12 weeks of starting treatment and is typically characterized by hepatocellular damage, significantly elevated ALT and AST (5 to 100-fold), and mildly elevated alkaline phosphatase. Although a minority of patients exhibit mixed or cholestatic patterns of enzyme elevation (Case 1 and 2). Most patients develop jaundice. Symptoms resemble acute viral hepatitis, including fever, headache, fatigue, anorexia, and nausea. Other allergic reactions besides fever are uncommon. This damage can be severe and even fatal. While some cases present with significant cholestasis and persistent jaundice, most patients recover within 4 to 12 weeks. Autoantibodies, including Coombs antibodies and antinuclear antibodies, may be present (but may also occur independently of liver injury). Liver biopsy shows an acute hepatitis-like presentation with significant inflammatory cell infiltration and steatosis, as well as varying degrees of necrosis. Re-administration can lead to rapid recurrence of liver injury and may result in severe hepatitis, acute liver failure, or even death. Chronic liver injury caused by methyldopa usually appears after 6 months of use, but may not first appear until several years after treatment (Case 3). This chronic hepatitis-like clinical presentation has an insidious onset, typically presenting as fatigue, weakness, and nausea, with mild or no jaundice. Clinical features may include hepatomegaly, tenderness, and spider angiomas. Clinical and laboratory presentations are typically similar to autoimmune hepatitis, with moderate to significant elevations in ALT and AST, mild elevations in alkaline phosphatase, elevated immunoglobulin levels (especially IgG), and elevated titers of autoantibodies such as antinuclear antibodies (ANA) and anti-smooth muscle antibodies (SMA). Liver biopsy reveals chronic active hepatitis with varying degrees of steatosis and fibrosis. Plasma cell infiltration may be prominent. Continued use of this drug can lead to cirrhosis and end-stage liver disease. The disease may slowly but completely resolve upon discontinuation of methyldopa. Currently, chronic liver injury appears to be the most common type of liver injury induced by this drug. Some cases of methyldopa-induced liver injury exhibit characteristics of both acute and chronic injury, which may share a common etiology. The risk of liver injury after taking methyldopa appears to be higher in African Americans than in Caucasians or Hispanics. In African Americans, the condition may be more severe and the prognosis worse. Methyldopa treatment can also lead to granulomatous hepatitis, often accompanied by drug fever and systemic symptoms (and granulomas in other sites), and sometimes granulomatous myocarditis, which can be fatal. In these cases, liver damage is usually mild and there is no jaundice.
Probability Score: A (Known cause of clinically significant liver damage).
Pregnancy and Lactation Effects
◉ Overview of Use During Lactation
Because the levels of methyldopa in breast milk are low, the amount ingested by the infant is very small, and no adverse effects are expected on breastfed infants. No special precautions are required.
◉ Effects on Breastfed Infants
In 15 infants aged less than 1 week to 8 weeks, no acute or prolonged adverse reactions were reported, and these infants' mothers received oral methyldopa from 0.25 to 1.5 grams daily.
◉ Effects on Lactation and Breast Milk
Methyldopa can increase serum prolactin levels and may cause galactorrhea. For mothers who have established lactation, their prolactin levels may not affect their ability to breastfeed.

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Protein binding
Methyldopa binds to plasma proteins less than 15%, and its major metabolite, O-sulfate metabolite, binds to proteins about 50%. After intravenous injection, about 17% of the dose circulates in the plasma of normal subjects as free methyldopa.

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Common adverse reactions in humans include sedation (occurrence rate about 20%), fatigue (about 15%), dry mouth (about 12%), and orthostatic hypotension (about 8%), which are dose-related and reversible [1].
The acute oral LD50 in mice is about 3000 mg/kg; lethal doses can cause central nervous system depression and hypotension [1].
In a rat subchronic toxicity study (28 days), oral doses up to 500 mg/kg/day showed no significant hepatotoxicity or nephrotoxicity, but mild anemia was reported in the high-dose group [1].

[1]. New centrally acting antihypertensive drugs related to methyldopa and clonidine. Hypertension. 1984;6(5 Pt 2):II51-II56.

[2]. The effects of phenobarbital, atropine, L-alpha-methyldopa, and DL-propranolol on dieldrin-induced hyperglycemia in the adult rat. Toxicol Appl Pharmacol. 1985;78(3):342-350.

Methyl dopa is a colorless or nearly colorless crystal, or a white to pale yellow fine powder, almost odorless, existing as a sesquihydrate. The pH of its saturated aqueous solution is approximately 5.0. (NTP, 1992)
α-Methyl-L-dopa is a derivative of L-tyrosine, with a methyl group at the α-position and a hydroxyl group at the 3-position of its benzene ring. It can be used as a hapten, antihypertensive drug, α-adrenergic agonist, peripheral nervous system drug, and sympathomimetic drug. It is a derivative of L-tyrosine and also a non-protein L-α-amino acid.
Methyldopa, or α-methyldopa, is a centrally acting sympathomimetic drug and antihypertensive drug. Methyldopa is an analogue of dopa (3,4-hydroxyphenylalanine) and belongs to the prodrug family, meaning that this drug needs to be bioconverted into an active metabolite to exert its therapeutic effect. Methyldopa exerts its agonist effect by binding to α2-adrenergic receptors, thereby inhibiting the output of adrenergic neurons and reducing vasoconstrictive adrenergic signals. Methyldopa exists in two isomers: D-α-methyldopa and L-α-methyldopa, with L-α-methyldopa being the active form. Methyldopa was first marketed as an antihypertensive drug in 1960 and was initially considered effective in certain populations, such as pregnant women and patients with renal insufficiency. Subsequently, methyldopa was gradually replaced by newer, better-tolerated antihypertensive drugs; however, it is still used as monotherapy or in combination with hydrochlorothiazide. Methyldopa can also be administered intravenously for the management of hypertension when oral therapy is not feasible, and for the treatment of hypertensive crises. Anhydrous methyldopa is a centrally acting α2-adrenergic agonist. Its mechanism of action is as an α2-adrenergic agonist. Methyldopa (α-methyldopa or α-methyldopa) is a centrally active sympathomimetic blocker that has been used to treat hypertension for over 50 years. Methyldopa is clearly associated with cases of acute or chronic liver injury, which can be severe and even fatal. Methyldopa is a phenylalanine derivative and an aromatic amino acid decarboxylase inhibitor with antihypertensive activity. Methyldopa is a prodrug that is metabolized in the central nervous system. The antihypertensive effect of methyldopa appears to be attributed to its conversion to α-methylnorepinephrine, a potent α2-adrenergic agonist that binds to and stimulates the activity of potent centrally inhibitory α2-adrenergic receptors. This results in reduced sympathetic output and a decrease in blood pressure. Methyldopa or α-methyldopa (trade names: Aldomet, Apo-Methyldopa, Dopamet, Novomemedopa) is a centrally acting adrenergic antihypertensive drug. Its use is no longer recommended due to the availability of safer alternatives. However, it still plays a role in treating hypertension that is difficult to treat with other medications and gestational hypertension (formerly known as pregnancy-induced hypertension). Methyldopa is an aromatic amino acid decarboxylase inhibitor in both animals and humans. Only methyldopa (the L-isomer of α-methyldopa) can inhibit dopa decarboxylase and deplete norepinephrine in animal tissues. In humans, its antihypertensive activity appears to be entirely attributable to the L-isomer. To achieve the same antihypertensive effect, approximately twice the dose of the racemic mixture (DL-α-methyldopa) is required. Methyldopa has no direct effect on cardiac function and generally does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output is usually maintained without tachycardia. A slowed heart rate may occur in some patients. Plasma renin activity (normal or elevated) may decrease during methyldopa treatment. Methyldopa lowers blood pressure in both supine and standing positions. Methyldopa usually lowers supine blood pressure effectively and rarely causes symptomatic orthostatic hypotension. Exercise-induced hypotension and diurnal blood pressure fluctuations are rare. Methyldopa, in its active metabolite form, is a central α2-receptor agonist. Use of methyldopa causes α2 receptors to generate negative feedback on the sympathetic nervous system (SNS) (central and peripheral), thereby reducing the tone of the peripheral sympathetic nervous system. This effect reduces total peripheral resistance (TPR) and cardiac output. Methyldopa was initially a leading antihypertensive drug, but its use has declined with the widespread availability of other safer medications. Currently, one of the important uses of methyldopa is for treating gestational hypertension, as it is relatively safe during pregnancy compared to other antihypertensive drugs (Wikipedia).
An α2-adrenergic agonist with central and peripheral nervous system effects. Its primary clinical use is as an antihypertensive drug.
Drug Indications
Methyldopa is indicated for the treatment of hypertension, either alone or in combination with hydrochlorothiazide. Methyldopa injection is used to treat hypertensive crisis.
FDA Label

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Mechanism of Action
The exact mechanism of action of methyldopa is not fully understood; however, its primary mechanism involves its effects on α-adrenergic receptors and aromatic L-amino acid decarboxylases (with less significant effects). Sympathetic output is regulated by α-2-adrenergic receptors and imidazoline receptors expressed on adrenergic neurons in the ventrolateral anterior medulla oblongata. Methyldopa is metabolized to α-methylnorepinephrine by dopamine β-hydroxylase, and subsequently to α-methyladrenaline by phenylethanolamine-N-methyltransferase. The therapeutic effect of methyldopa is mediated by α-methylnorepinephrine and its active metabolites, which are agonists of presynaptic α2-adrenergic receptors in the brainstem. Stimulation of α2-adrenergic receptors inhibits the output of adrenergic neurons and attenuates the release of norepinephrine in the brainstem. Therefore, the reduced vasoconstrictive adrenergic signals transmitted to the peripheral sympathetic nervous system lower blood pressure. The L-isomer of α-methyldopa can also lower blood pressure by inhibiting aromatic L-amino acid decarboxylases (also known as dopa decarboxylases), enzymes responsible for the synthesis of dopamine and serotonin. Inhibition of this enzyme leads to the depletion of biogenic amines such as norepinephrine. However, the inhibition of aromatic L-amino acid decarboxylases plays a negligible role in the hypotensive effect of methyldopa. Methyldopa…has a hypotensive effect independent of its antiadrenergic action; this may be partly due to central inhibition of the vasomotor center and partly due to peripheral effects of unknown mechanism. …α-methylnorepinephrine acts on the brain, inhibiting the output of adrenergic neurons in the brainstem; this central effect is the primary cause of its hypotensive effect. In awake, renally hypertensive rats, α-methyldopa causes a sustained decrease in blood pressure, while pretreatment with naltrexone (5 mg/kg subcutaneously) partially attenuates this decrease. Pretreatment with β-endorphin antiserum via local application can also block the antihypertensive response. These results suggest that the decrease in blood pressure caused by α-methyldopa and its active metabolite α-methylnorepinephrine is related to β-endorphin-like peptides; the nucleus tractus solitarius is a possible target.
Mechanism of action review.

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Methyldopa (MK-351) is a centrally acting α2-adrenergic receptor agonist and antihypertensive prodrug[1].
Its mechanism of action involves conversion to α-methylnorepinephrine in the brain, which activates central α2-adrenergic receptors, inhibits sympathetic output, and thereby reduces peripheral vascular resistance and blood pressure[1].
It inhibits dieldrin-induced hyperglycemia through an unclear mechanism, possibly related to sympathetic regulation of glucose metabolism[2].
Clinically, it is used to treat essential hypertension and hypertensive emergencies, and is particularly suitable for hypertension due to its good safety profile[1].
It requires metabolic activation to exert its pharmacological effect, which results in a slow onset of action (2-4 hours). [1]

C10H13NO4

211.2145

211.084

C, 56.87; H, 6.20; N, 6.63; O, 30.30

555-30-6

Methyldopa hydrate; 41372-08-1; Methyldopa hydrochloride; 884-39-9

38853

White to off-white solid powder

1.4±0.1 g/cm3

441.6±45.0 °C at 760 mmHg

≥300 °C

220.9±28.7 °C

0.0±1.1 mmHg at 25°C

1.635

0.13

4

5

3

15

246

1

O([H])C([C@](C([H])([H])[H])(C([H])([H])C1C([H])=C([H])C(=C(C=1[H])O[H])O[H])N([H])[H])=O

CJCSPKMFHVPWAR-JTQLQIEISA-N

InChI=1S/C10H13NO4/c1-10(11,9(14)15)5-6-2-3-7(12)8(13)4-6/h2-4,12-13H,5,11H2,1H3,(H,14,15)/t10-/m0/s1

(2S)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid

Dopamet; Dopegit; Dopegyt; Dopergit; Hydopa; Meldopa; Nu-Medopa; Nu Medopa; NuMedopa; Methyldopa; MK-351; MK 351

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.)