Methyldopa hydrate (L-(-)-α-methyldopa hydrate; 200 mg/kg; intraperitoneally) lessens the hyperglycemic reaction within the first two hours following dieldrin administration [2].

Animal/Disease Models: 60-day-old male rats [2]
Doses: 200 mg/kg
Route of Administration: intraperitoneal (ip) injection
Experimental Results: Within 30 minutes after administration, plasma glucose concentrations in rats exposed to dieldrin diminished by 24 %.

Absorption, Distribution and Excretion
Methyldopate 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 Methyldopate 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 Methyldopate is excreted in the urine as the unchanged drug (24%) and α-Methyldopate mono-O-sulfate (64%), but individual differences exist. 3-O-methyl-α-Methyldopate accounts for approximately 4% of the urinary excretions. Other metabolites, such as 3,4-dihydroxyphenylacetone, α-Methyldopatemine, and 3-O-methyl-α-Methyldopatemine, 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 Methyldopate 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-Methyldopate to hypertensive patients, the recovery rates from urine and feces are equal. The product in feces is unaltered Methyldopate, and the product in urine is Methyldopate and its ethyl sulfate, as well as small amounts of 3-O-methylMethyldopate and Methyldopatemine.
Methyldopate can cross the placental barrier…
Methyldopate 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 Methyldopate undergo different metabolic pathways. L-α-Methyldopate is bioconverted to its pharmacologically active metabolite, α-methylnorepinephrine. Methyldopate is extensively metabolized in the liver, producing the main circulating metabolite in plasma—α-Methyldopate mono-O-sulfate. Other metabolites include 3-O-methyl-α-Methyldopate, 3,4-dihydroxyphenylacetone, α-Methyldopatemine, and 3-O-methyl-α-Methyldopatemine. These metabolites are further conjugated in the liver to form sulfate conjugates. After intravenous administration, the most significant metabolites are glucuronide of α-Methyldopatemine and dihydroxyphenylacetone, along with several other unidentified metabolites. The inactive isomer of Methyldopate, D-α-Methyldopate, is also metabolized to small amounts of 3-O-methyl-α-Methyldopate and 3,4-dihydroxyphenylacetone. However, no amines (α-Methyldopatemine and 3-O-methyl-α-Methyldopatemine) are formed. Methyldopate 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/ Methyldopate in the mouse and rabbit brains undergoes decarboxylation and β-hydroxylation to produce α-methylnorepinephrine.
……After intraperitoneal injection into rats, (14)C-Methyldopate was excreted in the urine. Its metabolites include: 3-O-methyl-Methyldopate (14%), Methyldopate and its conjugates (2%), 3-O-methyl-Methyldopate and its conjugates (6%), 3-methoxy-4-hydroxyphenylacetone (6%), and 3,4-dihydroxyphenylacetone (10%).
A review of α-Methyldopate metabolism.
Mainly metabolized by the liver. Known urinary metabolites include: α-Methyldopate mono-O-sulfate; 3-O-methyl-α-Methyldopate; 3,4-dihydroxyphenylacetone; α-Methyldopate; 3-O-methyl-α-Methyldopate and its conjugates.
Excretion pathway: Methyldopate is widely metabolized. Known urinary metabolites include: α-Methyldopate mono-O-sulfate; 3-O-methyl-α-Methyldopate; 3,4-dihydroxyphenylacetone; α-Methyldopatemine; 3-O-methyl-α-Methyldopatemine and its conjugates. Approximately 70% of the absorbed drug is excreted in the urine as Methyldopate and its mono-O-sulfate conjugate. Methyldopate can cross the placental barrier and is found in umbilical cord blood and breast milk. Half-life: The plasma half-life of Methyldopate is 105 minutes. Following intravenous administration, the plasma half-life of Methyldopate 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 Methyldopate 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. Renal excretion accounts for approximately two-thirds of the drug cleared from the plasma. In patients with severely impaired renal function, only about 50% of the drug is excreted in the early stages (half-life = 3.5 hours), and drug accumulation may occur during long-term use… Significant differences may exist between individuals and between different dates within the same patient in total drug absorption and the distribution of metabolites in urine.

Toxicity Summary
Identification: Methyldopate is a colorless or nearly colorless crystal, or a white to pale yellow fine powder, which may contain brittle fragments. Slightly soluble in water and ethanol; practically insoluble in chloroform and ether; soluble in dilute mineral acids. Practically insoluble in common organic solvents. Indications: Used to treat moderate to severe hypertension, usually in combination with diuretics or beta-blockers. Methyldopate has also been used to treat severe movement disorders. Human Exposure: Major Risks and Target Organs: Acute Overdose: Target organs are the central nervous system and cardiovascular system. Major risks include hypotension, bradycardia, arrhythmias, and hypothermia. Chronic Poisoning and Adverse Reactions: Target organs are the central nervous system, cardiovascular system, liver, pancreas, and immune system. Acute: Drowsiness, coma, hypotension, bradycardia, dry mouth, atrioventricular block, and hypothermia. Chronic: Central nervous system effects: sedation, Parkinson's syndrome, choreoathetosis, headache, and dizziness. Cardiovascular effects: bradycardia, prolonged carotid sinus hypersensitivity, myocarditis, pericarditis, worsening angina, orthostatic hypotension, first-degree atrioventricular block. Gastrointestinal effects: diarrhea, colitis, dry mouth, black tongue, reversible malabsorption, pancreatitis. Liver disease: hepatitis. Allergic reactions: rash, urticaria, eczema, lichenoid rash. Hematologic effects: positive Coombs test, leukopenia, hemolysis. Contraindications: active liver disease, such as acute hepatitis and active cirrhosis. Methyldopate is not recommended for patients with pheochromocytoma. In rare cases, patients with severe bilateral cerebrovascular disease may experience involuntary choreoathetosis during Methyldopate treatment; these patients should avoid Methyldopate. Elderly patients with advanced atherosclerosis should have a reduced dose of Methyldopate to avoid syncope. Methyldopate should be used with caution in patients with impaired renal function or depression. Methyldopate has been reported to worsen porphyria. Oral administration: Intentional high doses may occur. Methyldopate is absorbed via active amino acid transport upon oral administration. Absorption of Methyldopate in the gastrointestinal tract is incomplete and varies considerably between individuals. Oral bioavailability varies considerably between individuals (50%). Peak plasma concentrations occur 2 to 3 hours later. Plasma concentrations of Methyldopate are not correlated with its clinical efficacy. Methyldopate can cross the placental barrier. Methyldopate can cross the blood-brain barrier. The entry of Methyldopate into the central nervous system is clearly an active transport process. Methyldopate is partially bound to various substances, primarily Methyldopate-O-sulfate. Except in patients with renal failure, this major metabolite may contribute little to the therapeutic effect. Other metabolites include Methyldopatemine, methylnorepinephrine, and O-methylated compounds. Methyldopate is excreted by the kidneys. Its elimination is phased. 95% of the drug is eliminated in the initial phase, with a half-life of 0.21 hours. In the second phase, the average half-life is 1.28 hours. 25% of unmetabolized Methyldopate is excreted in the urine within 24 hours. Methyldopate reduces vascular resistance. The most significant decrease in arterial blood pressure occurs 6 to 8 hours after oral administration. Concomitant use with diuretics, other antihypertensive drugs, and general anesthetics can worsen hypotension. Concomitant use of Methyldopate with digoxin may cause symptomatic sinus bradycardia. Concomitant use of Methyldopate with lithium carbonate appears to induce symptoms of lithium poisoning. Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the effect of Methyldopate. Central nervous system depressants, including alcohol and narcotic analgesics, can enhance the antihypertensive effect of Methyldopate, even to dangerous levels. Concomitant use of Methyldopate with sedatives, hypnotics, tranquilizers, or other central nervous system depressants may further suppress the central nervous system. The antihypertensive effect of Methyldopate may be inhibited by amphetamines and other sympathomimetic drugs, monoamine oxidase inhibitors, and tricyclic antidepressants. Methyldopate may enhance the hypoglycemic effect of tolbutamide. Methyldopate may prolong prothrombin time when used in combination with anticoagulants. Methyldopate may reduce the effect of ephedrine because it decreases norepinephrine levels in sympathetic nerve endings. Concomitant use of Methyldopate with haloperidol and chlorpromazine may cause psychomotor retardation, memory loss, and poor concentration. Concomitant use of Methyldopate with monoamine oxidase inhibitors may cause headache and hypertension. Other side effects include sedation, headache, fatigue, drowsiness, depression, decreased mental acuity, poor concentration, memory loss, nightmares, nausea, dry mouth, nasal congestion, dizziness, vertigo, edema, sexual dysfunction, weight gain, orthostatic hypotension with dizziness. Other side effects include breast enlargement, galactorrhea, hyperprolactinemia, black tongue or glossitis, salivary gland inflammation, pancreatitis, paresthesia, Bell's palsy, Parkinson's syndrome, diarrhea, constipation, fever, arthralgia, myalgia, uremia, myocarditis, worsening angina, bradycardia, and atrioventricular block. Paradoxical pressor reactions have been observed following intravenous administration of Methyldopate hydrochloride. Rebound hypertension has been reported after abrupt discontinuation of the oral medication. This drug has been reported to cause thrombocytopenia, leukopenia, granulocytopenia, hemolytic anemia, as well as fever, jaundice, and liver damage. Other adverse reactions include systemic lupus erythematosus-like syndrome, rash, urticaria, eczema, and hyperkeratosis. Rare central nervous system adverse reactions include reversible mild psychosis, depression, and blurred vision. Although its mechanism of action is not fully understood, its antihypertensive effect is likely due to its effects on the central nervous system. Methyldopate is converted to the metabolite α-methylnorepinephrine in the central nervous system, which stimulates central inhibitory α-adrenergic receptors, thereby reducing sympathetic tone, total peripheral resistance, and blood pressure. Decreased plasma renin activity and inhibition of central and peripheral norepinephrine and serotonin production may also contribute to the drug's antihypertensive effect, although this is not its primary mechanism of action. This is achieved by inhibiting the decarboxylation of dihydroxyphenylalanine (DOPA, a precursor of norepinephrine) and 5-hydroxytryptophan (5-HTP, a precursor of serotonin) in the central nervous system and most peripheral tissues.

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Toxicity Data
LD50: >1.5 g/kg (oral, mouse) (A308)
LD50: >1.5 g/kg (oral, rat) (A308)

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Interactions
Levodopa has been reported to enhance the hypotensive effect of Methyldopate in humans.
The acute hypotensive effect of Methyldopate has been reported to be eliminated by pretreatment with toxapine, imipramine, and intraventricular injection of toxapine. 6-Hydroxydopa, and its effect can be enhanced by the monoamine oxidase inhibitor trans-cyclopropylamine. Hypotension…can be blocked by intraventricular injection of a small dose of phentolamine…
Methyldopate has been reported to enhance amphetamine-induced hyperactivity in mice…
Phenobarbital has been reported to induce the metabolism of Methyldopate when these drugs are used concomitantly. Related drugs—other barbiturates are expected to have similar effects to phenobarbital.
For more complete data on interactions of Methyldopate (18 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 5000 mg/kg
Intraperitoneal LD50 in rats: 300 mg/kg
Intraperitoneal LD50 in mice: 150 mg/kg
Intravenous LD50 in mice: 1700 mg/kg
For more complete data on non-human toxicity values of Methyldopate (6 in total), please visit the HSDB record page.

[1]. Sweet CS. 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.

Therapeutic Uses
Methyldopate is indicated for the treatment of moderate to severe hypertension, including hypertension with kidney disease. /US product label includes/ Methyldopate is an effective antihypertensive agent when used in combination with diuretics. The usual starting dose of Methyldopate is 250 mg twice daily; doses exceeding 2 g appear to have no additional effect. For more complete data on the therapeutic uses of Methyldopate (6 items in total), please visit the HSDB record page. Drug Warnings Methyldopate should be used with caution in patients with a history of liver disease or impaired liver function. It is not recommended for patients with pheochromocytoma. Methyldopate is contraindicated in patients with active liver disease (e.g., acute hepatitis and active cirrhosis) and in patients with liver abnormalities or hemolytic anemia with a positive direct antiglobulin test (Coombs test) due to prior Methyldopate treatment. Methyldopate is contraindicated in patients taking monoamine oxidase (MAO) inhibitors.
Patients receiving Methyldopate treatment and undergoing dialysis may occasionally experience hypertension after dialysis, as the drug is removed via dialysis.
It has been reported that approximately 10-20% of patients treated with Methyldopate develop a positive direct antiglobulin test (Coombs test) after 6-12 months of treatment. This phenomenon is dose-related, with the lowest incidence in patients taking 1 gram or less of Methyldopate daily. For most patients, a positive Coombs test related to Methyldopate treatment is not clinically significant. A positive Coombs test result will turn negative within weeks to months after discontinuation of the drug, usually within 6 months. The incidence of hemolytic anemia is low, but there have been two reported deaths from Methyldopate-induced hemolytic anemia. If anemia or a positive Coombs test occurs, appropriate laboratory tests should be performed to determine the presence of hemolysis; if there is evidence of hemolytic anemia, the drug should be discontinued. Discontinuation of the drug alone or initiation of corticosteroid therapy can alleviate Methyldopate-induced hemolytic anemia.
Nasal congestion is common in patients taking Methyldopate. Decreased libido and erectile dysfunction are common in men taking this medication. For more complete data on Methyldopate (16 in total), please visit the HSDB records page.

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Pharmacodynamics
The antihypertensive effect of Methyldopate is primarily mediated by its pharmacologically active metabolite, α-methylnorepinephrine, which acts as an agonist of centrally inhibitory α-adrenergic receptors. Stimulation of α-adrenergic receptors reduces peripheral sympathetic tone and lowers arterial blood pressure. Methyldopate results in a net decrease in the concentrations of serotonin, dopamine, norepinephrine, and epinephrine in tissues. Overall, Methyldopate lowers standing blood pressure, especially in the supine position, but symptomatic orthostatic hypotension is rare. Methyldopate reduces plasma renin activity, but has negligible effects on glomerular filtration rate, renal blood flow, or filtration fraction. It has no direct effect on cardiac function, but some patients may experience bradycardia. After oral administration, most patients experience a blood pressure-lowering effect within 12 to 24 hours, with the maximum reduction in blood pressure occurring within 4 to 6 hours. After discontinuation of the drug, blood pressure returns to pre-treatment levels within 24 to 48 hours. After intravenous injection, the blood pressure-lowering effect of Methyldopate lasts approximately 10 to 16 hours.

C20H32N2O11

476.47

476.2

41372-08-1

Methyldopa;555-30-6;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(lit.)

220.9±28.7 °C

0.0±1.1 mmHg at 25°C

1.635

0.13

4

5

3

15

246

1

C[C@](CC1=CC(=C(C=C1)O)O)(C(=O)O)N

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

Methyldopa; Hyperpax; Aldomet

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)

DMSO : ~25 mg/mL (~104.94 mM)
H2O : ~1 mg/mL (~4.20 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.49 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.49 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.49 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)