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
Methyldopa is incompletely absorbed from the gastrointestinal tract following oral administration. In healthy individuals, the inactive D-isomer is less readily absorbed than the active L-isomer. The mean bioavailability of methyldopa is 25%, ranging from eight to 62%. Following oral administration, about 50% of the dose is absorbed and Tmax is about three to six hours.
Approximately 70% of absorbed methyldopa is excreted in the urine as unchanged parent drug (24%) and α-methyldopa mono-O-sulfate (64%), with variability.3-O-methyl-α-methyldopa accounted for about 4% of urinary excretion products. Other metabolites like 3,4-dihydroxyphenylacetone, α-methyldopamine, and 3-O-methyl-α-methyldopamine are also excreted in urine. Unabsorbed drug is excreted in feces as the unchanged parent compound. After oral doses, excretion is essentially complete in 36 hours. Due to attenuated excretion in patients with renal failure, accumulation of the drug and its metabolites may occur, possibly leading to more profound and prolonged hypotensive effects in these patients.
The apparent volume of distribution ranges between 0.19 and 0.32L/kg and the total volume of distribution ranges from 0.41 to 0.72L/kg. Since methyldopa is lipid-soluble, it crosses the placental barrier, appears in cord blood, and appears in breast milk.
The renal clearance is about 130 mL/min in normal subjects and is decreased in patients with renal insufficiency.
(14)C-METHYLDOPA ADMIN ORALLY TO HYPERTENSIVE PT IS RECOVERED EQUALLY FROM URINE & FECES; PRODUCT IN FECES IS UNCHANGED METHYLDOPA, & IN URINE METHYLDOPA & ITS ETHEREAL SULFATE, TOGETHER WITH SMALL AMT OF 3-O-METHYL-METHYLDOPA & METHYLDOPAMINE.
METHYLDOPA CROSSES THE PLACENTA...
Methyldopa is partially absorbed from the GI tract. The degree of absorption varies among individuals and in the same patient from day to day, but generally about 50% of an oral dose is absorbed.

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Metabolism / Metabolites
Two isomers of methyldopa undergo different metabolic pathways. L-α-methyldopa is biotransformed to its pharmacologically active metabolite, alpha-methylnorepinephrine. Methyldopa is extensively metabolized in the liver to form the main circulating metabolite in the plasma, alpha (α)-methyldopa mono-O-sulfate. Its other metabolites also 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 prominent metabolites are alpha-methyldopamine and the glucuronide of dihydroxyphenylacetone, along with other uncharacterized metabolites. D-α-methyldopa, which is the inactive isomer of methyldopa, is also metabolized to 3-O-methyl-α-methyldopa and 3,4-dihydroxyphenylacetone to a minimal extent; however, there are no amines (α-methyldopamine and 3-O-methyl-α-methyldopamine) formed.
METHYLDOPA YIELDS 3,4-DIHYDROXY-ALPHA-METHYLPHENETHYLAMINE, 3,4-DIHYDROXY-ALPHA-METHYL-L-PHENYLALANINE-O-SULFATE, & 4-HYDROXY-3-METHOXY-ALPHA-METHYL-L-PHENYLALANINE IN MAN. /FROM TABLE/
METHYLDOPA...UNDERGOES DECARBOXYLATION & BETA-HYDROXYLATION IN MOUSE & RABBIT BRAIN TO YIELD ALPHA-METHYLNORADRENALINE.
...ADMIN IP TO RATS (14)C-METHYLDOPA IS EXCRETED IN URINE AS...3-O-METHYL-METHYLDOPA (14%), METHYLDOPAMINE & ITS CONJUGATES (2%), 3-O-METHYL-METHYLDOPAMINE & ITS CONJUGATES (6%), 3-METHOXY-4-HYDROXYPHENYLACETONE (6%), & 3,4-DIHYDROXYPHENYLACETONE (10%).
A REVIEW ON THE METAB OF ALPHA-METHYLDOPA.
Hepatic, extensively metabolized. The known urinary metabolites are: a-methyldopa mono-0-sulfate; 3-0-methyl-a-methyldopa; 3,4-dihydroxyphenylacetone; a-methyldopamine; 3-0-methyl-a-methyldopamine and their conjugates.
Route of Elimination: Methyldopa is extensively metabolized. The known urinary metabolites are: alpha-methyldopa mono-O-sulfate; 3-0-methyl-alpha-methyldopa; 3,4-dihydroxyphenylacetone; alpha-methyldopamine; 3-0-methyl-alpha-methyldopamine and their conjugates. Approximately 70 percent of the drug which is absorbed is excreted in the urine as methyldopa and its mono-O-sulfate conjugate. Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk.
Half Life: The plasma half-life of methyldopa is 105 minutes.

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Biological Half-Life
The plasma half-life of methyldopa is 105 minutes. Following intravenous injection, the plasma half-life of methyldopa ranges from 90 to 127 minutes.
The drug is ... eliminated with a half-life of about 2 hr. ... The half-life of methyldopa is prolonged to 4-6 hr in patients with renal failure.
DISAPPEARANCE OF THE DRUG FROM PLASMA AFTER IV ADMIN IS BIPHASIC, & THE TERMINAL HALF-TIME OF ELIMINATION FROM PLASMA IS ABOUT 2 HOURS. RENAL EXCRETION ACCOUNTS FOR ABOUT TWO THIRDS OF THE CLEARANCE OF DRUG FROM PLASMA.
IN PT WITH SEVERELY IMPAIRED RENAL FUNCTION, ONLY ABOUT 50% OF DRUG IS EXCRETED DURING EARLY PHASE (T/2= 3 1/2 HR), & SOME ACCUMULATION CAN OCCUR DURING CHRONIC ADMIN... BOTH TOTAL QUANTITY ABSORBED & DISTRIBUTION OF METABOLITES IN URINE CAN VARY CONSIDERABLY IN DIFFERENT INDIVIDUALS & IN SAME PT FROM DAY TO DAY.

Toxicity Summary
IDENTIFICATION: Methyldopa is a colorless or almost colorless crystal or a white to yellowish-white fine powder which may contain friable lumps. Slightly soluble in water and alcohol; practically insoluble in chloroform and ether; dissolves in dilute mineral acids. Practically insoluble in the common organic solvents. Indications: Treatment of moderate to severe hypertension usually in combination with diuretic or a beta-blocking agent. Methyldopa has been used in the treatment of severe dyskinesias. HUMAN EXPOSURE: Main risks and target organs: Acute overdose: the target organs are the central nervous system and the cardiovascular system. The main risks are hypotension, bradycardia, cardiac arrhythmia and hypothermia. Chronic poisoning and adverse effects: the target organs are the central nervous system, cardiovascular system, liver, pancreas and immunological system. Acute: drowsiness, coma, hypotension, bradycardia, dry mouth, impairment of atrioventricular conduction, and hypothermia. Chronic: CNS manifestations: sedation, parkinsonism, choreoathetoid movements, headache and vertigo. Cardiovascular effects: bradycardia, prolonged carotid sinus hypersensitivity, myocarditis, pericarditis, aggravation of angina pectoris, postural hypotension, first-degree heart block. Gastrointestinal effects diarrahea, colitis, dryness of the mouth, black tougue, reversible malabsorption, pancreatitis. Liver disorders: hepatitis. Hypersensitivity reactions: rash, urticaria, eczema, lichenoid eruptions. Hematological manifestations : positive Coomb's test, leucopenia, hemolysis. Contraindications: Active hepatic disease, such as acute hepatitis and active cirrhosis.Methyldopa is not recommended for patients with pheochromocytoma. Rarely, involuntary choreoathetoid movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease should avoid methyldopa. Older patients with advanced arteriosclerotic disease should be given lower dose of methyldopa to avoid syncope. Methydopa should be used with caution in patients with impaired kidney function or mental depression. Methydopa has been reported to aggravate porphyria. Oral : Intentional ingestion of large doses may occur. When administered orally, methyldopa is absorbed by an active amino acid transport. Methyldopa is incompletely and variably absorbed from the gastrointestinal tract. Oral bioavailability is variable (50%). Peak concentrations in plasma occur after 2 to 3 hours. Plasma level of methyldopa does not correlate with its clinical effect. Methyldopa crosses the placenta. Methyldopa crosses the blood brain barrier. The transport of methyldopa into CNS is apparently an active process. Methyldopa is partly conjugated, mainly to the methyldopa-O-sulfate. The major metabolite probably contributes little to the therapeutic effect except in patients with renal failure. Other metabolites include methyldopamine, methylnorepinephrine, and O-methylated compounds. Methyldopa is excreted by the kidneys. Elimination is phasic. 95% of the drug is eliminated in the initial phase with a half-life of 0.21 hour. In the second phase, the limitation half-life averages 1.28 hours. Twenty-five percent of unchanged methyldopa is excreted in the urine within 24 hours. Methyldopa reduces vascular resistance. The fall in arterial pressure is maximal 6 to 8 hours after an oral. Hypotension can be increased by concurrent administration of diuretics and other antihypertensive agents, and general anesthetics. Concomittant use of methyldopa and digoxin may produce symptomatic sinus bradycardia. Concomitant use of metyldopa and lithium carbonate appeared to induce signs of lithium toxicity.The action of methyldopa may be decreased by simultaneous use of non-steroidal anti-inflamatory agents. CNS depressants including alcohol and narcotic analgesics, may potentiate the hypotensive action of methyldopa to a dangerous degree. When methyldopa is administered with sedatives, hypnotics, tranquilizers, or other central nervous system depressants, further central nervous system depression may occur. The hypotensive action of methyldopa may be inhibited by amphetamines and other sympathomimetic drugs, monoamine oxidase inhibitors, and tricyclic antidepressants. Methyldopa may increase the hypoglycemic effects of tolbutamide. Methyldopa may increase prothrombin time if added to treatment with anticoagulants. Methyldopa may decrease the effect of ephedrine, since it reduces the quantity of norepinephrine in sympathetic nerve endings. Methyldopa used with haloperidol and chlorpromazine may produce psychomotor retardation, memory impairment, and inability to concentrate. Methyldopa used with monoamine oxidase inhibitor drugs may produce headache and hypertension. Sedation, headache, asthenia, drowsiness, depression, impaired mental acuity, impaired ability to concentrate, lapses of memory, nightmares, nausea, dryness of the mouth, nasal stuffiness, dizziness, vertigo, edema, disorders of sexual function, weight gain, orthostatic hypotension with lightheadedness. Breast enlargement, lactation, hyperprolactinemia, black or sore tongue, salivary gland inflammation, pancreatitis, paresthesias, Bell's palsy, parkinsonism, diarrhea, constipation, fever, arthralgia, myalgia, uremia, myocarditis, aggravation of angina pectoris, bradycardia, atrioventricular conduction disturbances. A paradoxical pressor response is seen after intravenous methyldopate hydrochloride. Rebound hypertension has been reported after abrupt withdrawal of oral administration. Thrombocytopenia, Leucopenia, granulocytopenia, hemolytic anemia have been reported along with fever, jaundice and liver damage. Systemic lupus erythematosus like syndrome, rash, urticarria, eczema and hyperkeratosis. Infrequent CNS effects include reversible mild psychosis, depression blurred vision.
Although the mechanism of action has yet to be conclusively demonstrated, the resultant hypotensive effect is most likely due to the drug's action on the CNS. Methyldopa is converted into the metabolite, alpha-methylnorepinephrine, in the CNS, where it stimulates the central inhibitory alpha-adrenergic receptors, leading to a reduction in sympathetic tone, total peripheral resistance, and blood pressure. Reduction in plasma renin activity, as well as the inhibition of both central and peripheral norepinephrine and serotonine production may also contribute to the drug's antihypertensive effect, although this is not a major mechanism of action. This is done through the inhibition of the decarboxylation of dihydroxyphenylalanine (dopa) - the precursor of norepinephrine - and of 5-hydroxytryptophan (5-HTP) - the precursor of serotonin - in the CNS and in 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...REPORTED TO AUGMENT ANTIHYPERTENSIVE EFFECT OF METHYLDOPA IN MAN.
ACUTE HYPOTENSIVE EFFECT OF METHYLDOPA HAS BEEN REPORTED TO BE ABOLISHED BY PRETREATMENT WITH RESERPINE, IMIPRAMINE, & INTRAVENTRICULAR 6-HYDROXYDOPAMINE, & TO BE ENHANCED BY MONOAMINE OXIDASE INHIBITOR TRANYLCYPROMINE. HYPOTENSION...BLOCKED BY INTRAVENTRICULAR ADMIN OF SMALL DOSE OF PHENTOLAMINE...
METHYLDOPA...REPORTED TO AUGMENT AMPHETAMINE-INDUCED HYPERACTIVITY IN MICE...
PHENOBARBITAL REPORTEDLY MAY INDUCE METABOLISM OF METHYLDOPA WHEN THESE AGENTS ARE ADMIN CONCURRENTLY. ... RELATED DRUGS--OTHER BARBITURATES WOULD BE EXPECTED TO ACT SIMILARLY TO PHENOBARBITAL.
For more Interactions (Complete) data for METHYLDOPA (18 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 5000 mg/kg
LD50 Rat ip 300 mg/kg
LD50 Mouse ip 150 mg/kg
LD50 Mouse iv 1700 mg/kg
For more Non-Human Toxicity Values (Complete) data for METHYLDOPA (6 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
Adrenergic alpha-Agonists; Antihypertensive Agents; Sympatholytics
Methyldopa is indicated in the treatment of moderate to severe hypertension, including that complicated by renal disease. /Included in US product labeling/
Methyldopa is an effective antihypertensive agent when given in conjunction with a diuretic.
THE USUAL INITIAL DOSE OF METHYLDOPA IS 250 MG TWICE DAILY, AND THERE APPEARS TO BE LITTLE ADDNL EFFECT WITH DOSES OVER 2 G.
For more Therapeutic Uses (Complete) data for METHYLDOPA (6 total), please visit the HSDB record page.

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Drug Warnings
Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction and is not recommended for use in patients with pheochromocytoma. Methyldopa is contraindicated in patients with active hepatic disease, such as acute hepatitis and active cirrhosis, and in patients in whom previous methyldopa therapy was associated with liver abnormalities or direct Coombs' positive hemolytic anemia. Methyldopa is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors.
Patients who are receiving methyldopa and who undergo dialysis may occasionally become hypertensive after the dialysis, since the drug is dialyzable.
Positive direct antiglobulin (Coombs') test results have been reported in about 10-20% of patients receiving methyldopa, usually after 6-12 months of therapy. This phenomenon is dose related, with the lowest incidence in patients receiving 1 g or less of methyldopa daily. In most patients, a postive Coombs' test associated with mehtyldopa therapy is not clinically important. Reversal of the positive Coombs' test occurs within weeks to months after discontinuance of the drug and usually becomes negative within 6 months. Hemolytic anemia has only rarely occurred, although 2 deaths have been reported in patients with methyldopa-induced hemolytic anemia. If anemia or a positive Coombs' test occurs, appropriate laboratory studies should be performed to determine if hemolysis is present; if there is evidence of hemolytic anemia, the drug should be discontinued. Discontinuance of the drug alone or initiation of corticosteroid therapy has produced remission of methyldopa-induced hemolytic anemia.
Nasal congestion occurs commonly in patients receiving methyldopa. Decreased libido and impotence frequently occur in males during therapy with the drug.
For more Drug Warnings (Complete) data for METHYLDOPA (16 total), please visit the HSDB record page.

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Pharmacodynamics
Antihypertensive effects of methyldopa are mostly mediated by its pharmacologically active metabolite, alpha-methylnorepinephrine, which works as an agonist at central inhibitory alpha-adrenergic receptors. Stimulation of alpha-adrenergic receptors leads to decreased peripheral sympathetic tone and reduced arterial pressure. Methyldopa causes a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine. Overall, methyldopa lowers both standing blood pressure and especially supine blood pressure, with infrequent symptomatic postural hypotension. Methyldopa also reduces plasma renin activity but has negligible effects on glomerular filtration rate, renal blood flow, or filtration fraction. It also has no direct effect on cardiac function but in some patients, a slowed heart rate may occur. Following oral administration, blood-pressure-lowering effects are observed within 12 to 24 hours in most patients, and a maximum reduction in blood pressure occurs in 4 to 6 hours. Blood pressure returns to pre-treatment levels within 24 to 48 hours following drug discontinuation. Following intravenous administration, the blood-pressure-lowering effects of methyldopa last for about 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.)