Absorption, Distribution and Excretion
Midodrine is rapidly absorbed after oral administration. Peak plasma concentrations of the prodrug, desglycined midodrine, are reached approximately half an hour after administration. Metabolites reach peak plasma concentrations approximately 1 to 2 hours after administration. The absolute bioavailability of midodrine (calculated as desglycined midodrine) is 93%, unaffected by food. Due to the poor blood-brain barrier crossing, its effects on the central nervous system are expected to be minimal. Renal clearance = 385 mL/min The renal excretion of midodrine is negligible. The renal clearance of desglycined midodrine is approximately 385 mL/min, of which approximately 80% is cleared through active renal secretion. The actual mechanism of active secretion has not been studied, but it may be achieved through the alkaline secretion pathway responsible for the secretion of several other alkaline drugs. Midodrine hydrochloride is a prodrug; the therapeutic effect of oral midodrine is primarily attributed to its major metabolite, desglycined midodrine, which is formed by the deglycination of midodrine. After oral administration, midodrine hydrochloride is rapidly absorbed. The prodrug reaches peak plasma concentration approximately half an hour later and declines with a half-life of approximately 25 minutes; the metabolite reaches peak plasma concentration approximately 1 to 2 hours after administration of midodrine, with a half-life of approximately 3 to 4 hours. The absolute bioavailability of midodrine (calculated as deglycined midodrine) is 93%. The bioavailability of deglycined midodrine is not affected by food. The amount of deglycined midodrine generated after intravenous and oral administration of midodrine is approximately the same. Neither midodrine nor deglycined midodrine binds significantly to plasma proteins. Midodrine is an oral medication used to treat orthostatic hypotension. It is almost completely absorbed after oral administration and is converted to its active form, 1-(2',5'-dimethoxyphenyl)-2-aminoethanol (DMAE), through the cleavage of glycine residues. Intestinal H+-coupled peptide transporter 1 (PEPT1) can transport a variety of peptide drugs and has been used as a target molecule to improve the intestinal absorption of poorly absorbed drugs through amino acid modification. Since midodrine meets these requirements, we investigated whether it could serve as a substrate for PEPT1. Oocytes expressing PEPT1 showed significantly increased uptake of midodrine (but not DMAE) compared to oocytes injected with water. Midodrine uptake in Caco-2 cells was saturated and inhibited by various PEPT1 substrates. Midodrine absorption in the rat intestine was very rapid and significantly inhibited by the high-affinity PEPT1 substrate cyclocillin, as assessed by changes in the area under the plasma concentration-time curve and the maximum concentration at 30 minutes. Some amino acid derivatives of DMAE can be transported by PEPT1, and this transport depends on the modified amino acid. Unlike neutral substrates, cationic midodrine is uptaken in large quantities under alkaline pH conditions, and our recently reported PEPT1 14-state model can reproduce this pH profile. These results indicate that PEPT1 can transport midodrine and contribute to improving the drug's bioavailability; glycine modification of DMAE is ideal for DMAE prodrugs. Metabolism/Metabolites Although comprehensive metabolic studies have not been conducted, the deglycination of midodrine to deglycine midodrine appears to occur in multiple tissues, and both compounds are partially metabolized in the liver. We investigated human cytochrome P450 (CYP) isoenzymes that catalyze the oxidative metabolism of the active metabolite of midodrine, deglycine midodrine (DMAE). Recombinant human CYP2D6, 1A2, and 2C19 exhibited significant catalytic activity for the 5'-O-demethylation of DMAE. The O-demethylase activity of recombinant CYP2D6 was significantly higher than that of other CYP isoenzymes. Quinidine (a selective inhibitor of CYP2D6) inhibited O-demethylation of DMAE in mixed human microsomes by 86%, while selective inhibitors of other CYP enzymes showed no significant effect. Although the activity of CYP2D6 in PM microsomes is negligible, approximately 25% of mixed microsomes retain DMAE O-demethylase activity. Furazolidone (a selective inhibitor of CYP1A2) inhibits M-2 production in PM microsomes by 57%. Treatment of mixed microsomes with anti-CYP2D6 antibody inhibits approximately 75% of M-2 production, while PM microsomes show no significant inhibitory effect. In contrast, anti-CYP1A2 antibody inhibits 40% to 50% of the activity in PM microsomes. These results suggest that in human liver microsomes, CYP2D6 exhibits the highest catalytic activity for DMAE 5'-O-demethylation, while CYP1A2 shows lower catalytic activity. Although a comprehensive metabolic study has not yet been conducted, the deglycination of midodrine to deglycined midodrine appears to occur in multiple tissues, and both compounds are partially metabolized in the liver. Midodrine and deglycinate midodrine are not substrates of monoamine oxidase.
Biological Half-Life
The half-life of the metabolite is approximately 3 to 4 hours.
The plasma concentration of the prodrug reaches its peak approximately half an hour after administration of midodrine and declines over a half-life of approximately 25 minutes; while the metabolite reaches its peak plasma concentration approximately 1 to 2 hours after administration of midodrine, with a half-life of approximately 3 to 4 hours.

Interactions
Although there is no experimental evidence to support this, the high renal clearance of diglycylmidodrine (an alkaline drug) may be related to the active tubular secretion of the alkaline secretion system, which is also responsible for the secretion of drugs such as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Therefore, diglycylmidodrine may interact with these drugs. Midodrine hydrochloride has been used in patients receiving concurrent sodium-sparing steroid therapy (e.g., fludrocortisone acetate), regardless of salt supplementation. These patients should be closely monitored for the possibility of developing supine hypertension, which can be minimized by reducing the dose of fludrocortisone acetate or reducing salt intake before initiating midodrine hydrochloride treatment. Alpha-adrenergic blockers, such as prazosin, terazosin, and doxazosin, can antagonize the effects of midodrine hydrochloride.
The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine, or dihydroergotamine) may enhance or exacerbate the pressor effect of midodrine hydrochloride. Therefore, caution should be exercised when using midodrine hydrochloride in combination with drugs that cause vasoconstriction.
The use of midodrine hydrochloride in combination with cardiac glycosides may exacerbate or induce bradycardia, atrioventricular block, or arrhythmias.
A patient taking midodrine to treat orthostatic hypotension has been reported to develop transient severe hypertension within 2 minutes after injection of 1% lidocaine containing 1:100,000 U epinephrine. It is speculated that the patient's autonomic nervous system was extremely sensitive to the effects of local anesthetics, which was then superimposed by the systemic vasoactive effects of midodrine. Surgeons should minimize the use of vasoconstrictors in patients receiving midodrine treatment to avoid hypertensive complications.

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Non-human toxicity values
Oral LD50 in mice: 675 mg/kg
Oral LD50 in rats: 30–50 mg/kg
Oral LD50 in dogs: 125–160 mg/kg

Midodrine is an aromatic ether with the structure 1,4-dimethoxybenzene, substituted at the 2-position with 2-(glycineamino)-1-hydroxyethyl. It is a direct-acting sympathomimetic drug with selective alpha-adrenergic agonist activity, typically used as a peripheral vasoconstrictor in the form of its hydrochloride salt to treat certain hypotensive conditions. Its main active ingredient is its major metabolite, desglycinemidodrine. Desglycinemidodrine has various pharmacological effects, including as a prodrug, alpha-adrenergic agonist, sympathomimetic drug, and vasoconstrictor. It is a secondary alcohol, amino acid amide, and aromatic ether. Its structure is related to glycineamide and desglycinemidodrine. It is the conjugate base of midodrine (1+). It is an ethanolamine derivative belonging to the alpha-adrenergic agonist class. It is used as a vasoconstrictor to treat hypotension. Midodrine is an alpha-adrenergic agonist. The mechanism of action of midodrine is as an alpha-adrenergic agonist. Midodrine is a direct-acting prodrug and sympathomimetic drug with antihypertensive properties. Midodrine is converted to its active metabolite, desglycined midodrine, via a deglycinate reaction. Desglycined midodrine selectively binds to and activates α-1-adrenergic receptors in arterioles and venules. This leads to smooth muscle contraction, thereby increasing blood pressure. Desglycined midodrine has difficulty crossing the blood-brain barrier and therefore does not affect the central nervous system (CNS). It is an ethanolamine derivative belonging to the α-1-adrenergic agonist class. It is used as a vasoconstrictor to treat hypotension. See also: Midodrine hydrochloride (salt form). Drug Indications For the treatment of symptomatic orthostatic hypotension (OH). Mechanism of Action Midodrine is metabolized to its pharmacologically active metabolite, desglycined midodrine. Desglycined midodrine acts as an α1-adrenergic receptor agonist on arterioles and venules. Activation of the α1-adrenergic receptor signaling pathway leads to increased vascular tone and elevated blood pressure. Desglycined midodrine has been reported to have negligible effects on cardiac β-adrenergic receptors. Midodrine hydrochloride is metabolized to the active metabolite desglycined midodrine, an α1-adrenergic receptor agonist that works by activating α-adrenergic receptors in arterioles and venules, thereby increasing vascular tone and raising blood pressure. Desglycined midodrine does not stimulate cardiac β-adrenergic receptors. Desglycined midodrine has difficulty crossing the blood-brain barrier and therefore does not affect the central nervous system.
Therapeutic Use
The U.S. Food and Drug Administration (FDA) intends to revoke the marketing authorization for midodrine hydrochloride for the treatment of hypotension—orthostatic hypotension—because post-marketing studies required to validate the drug's clinical benefit have not been completed. To date, neither the original manufacturer nor any generic drug manufacturer has been able to demonstrate the drug's clinical efficacy, for example, by demonstrating that its use improves patients' activities of daily living.
...Used as a vasoconstrictor to treat hypotension
Midodrine hydrochloride is used to treat symptomatic orthostatic hypotension; this drug has been designated an orphan drug by the U.S. Food and Drug Administration (FDA) for this purpose. /U.S. product label contains/

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Drug Warning
Warning: Because midodrine hydrochloride tablets can significantly increase supine blood pressure, it should only be used in patients whose quality of life remains severely impaired after receiving standard clinical treatment. The indication for midodrine hydrochloride tablets in the treatment of symptomatic orthostatic hypotension is primarily based on changes in a surrogate endpoint of efficacy, namely an increase in systolic blood pressure measured one minute after standing, which is considered potentially related to clinical benefit. However, no clinical benefit of midodrine hydrochloride tablets has been established, primarily for improving activities of daily living.
The most potentially serious adverse reaction to midodrine hydrochloride treatment is a significant increase in supine arterial blood pressure (supine hypertension). In patients taking 10 mg of midodrine hydrochloride, approximately 13.4% experienced a systolic blood pressure of approximately 200 mmHg. This level of systolic blood pressure elevation is most likely to occur in patients with relatively high pre-treatment systolic blood pressure (average 170 mmHg). For patients with initial supine systolic blood pressure above 180 mmHg, experience is lacking as clinical trials have excluded such patients. Midodrine hydrochloride is not recommended for these patients. Midodrine hydrochloride treatment can also increase sitting blood pressure. Patients receiving midodrine hydrochloride treatment must have their supine and sitting blood pressure monitored. At the start of midodrine hydrochloride treatment, the likelihood of developing supine and sitting hypertension should be assessed. Supine hypertension can usually be controlled by avoiding complete supine positioning (e.g., elevating the head of the bed). Patients should be informed to report any symptoms of supine hypertension immediately. These symptoms may include palpitations, tinnitus, headache, blurred vision, etc. The use of midodrine hydrochloride in patients with hepatic impairment has not been studied. Midodrine hydrochloride should be used with caution in patients with hepatic impairment because the liver is involved in the metabolism of midodrine.
For more complete data on midodrine warnings (12 in total), please visit the HSDB record page.

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Pharmacodynamics
Midodrine is a prodrug; the therapeutic effect of oral midodrine is attributed to its major metabolite, deglycined midodrine, which is formed by the deglycation of midodrine. Midodrine can increase systolic and diastolic blood pressure in patients with orthostatic hypotension of various etiologies in standing, sitting, and supine positions. One hour after taking 10 mg of midodrine, standing systolic blood pressure increases by approximately 15 to 30 mmHg, and some effects can last for 2 to 3 hours. Midodrine has no clinically significant effect on standing or supine pulse rate in patients with autonomic dysfunction.

C12H18N2O4

254.286

254.127

42794-76-3

Midodrine hydrochloride;43218-56-0;Midodrine-d6 hydrochloride;1188265-43-1

4195

White to off-white solid powder

0.903

3

5

6

18

263

0

MGCQZNBCJBRZDT-PPHPATTJSA-N

InChI=1S/C12H18N2O4.ClH/c1-17-8-3-4-11(18-2)9(5-8)10(15)7-14-12(16)6-13/h3-5,10,15H,6-7,13H2,1-2H3,(H,14,16)1H/t10-/m0./s1

(R)-2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide hydrochloride

St-1085 St1085 St 1085Amatine Pro-AmatineOrvaten

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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.)