Adrenergic Receptor

Droxidopa was administered acutely to PVL and BDL rats, which resulted in a significant and sustained increase in arterial pressure and mesenteric arterial resistance, as well as a significant decrease in portal and mesenteric blood flow, without altering portal pressure or renal blood flow. Rats given dronipoma also displayed higher RhoK activity in SMA and a lower ratio of p-eNOS/eNOS and p-AKT/AKT[5].

250-380g male Sprague-Dawley rats
200 mg/kg (10 mg/kg, i.p. benserazide was given to the animals at 20 or 30 min prior to L-DOPS injection)
I.p.

Absorption, Distribution and Excretion
Oral bioavailability is 90%.
Droxidopa is mainly excreted in the urine, with the main metabolite being 3-O-methyldihydroxyphenylserine.

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Metabolism / Metabolites
Droxidopa is metabolized by aromatic L-amino acid decarboxylase.

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Biological Half-Life
2-3 hours.

Hepatotoxicity
Liver test abnormalities have not been reported in patients taking droxidopa, but the agent has had limited clinical use. There were no episodes of clinically apparent liver injury reported in the preregistration trials of droxidopa, and since its approval there have been no published reports of droxidopa hepatotoxicity. Thus, liver injury from droxidopa is likely to be rare, if it occurs at all.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

[1]. Clin Auton Res . 2008 Mar:18 Suppl 1:25-9.

[2]. Clin Auton Res . 2001 Aug;11(4):235-42.

[3]. Clin Auton Res . 2008 Mar:18 Suppl 1:19-24.

[4]. Cardiovasc Drug Rev . 2006 Fall-Winter;24(3-4):189-203.

[5]. Hepatology . 2012 Nov;56(5):1849-60.

Droxidopa is a serine derivative that is L-serine substituted at the beta-position by a 3,4-dihydroxyphenyl group. A prodrug for noradrenalone, it is used for treatment of neurogenic orthostatic hypotension It has a role as a prodrug, a vasoconstrictor agent and an antihypertensive agent. It is a L-tyrosine derivative and a member of catechols.
Droxidopa is a precursor of noradrenaline that is used in the treatment of Parkinsonism. It is approved for use in Japan and is currently in trials in the U.S. The racaemic form (dl-threo-3,4-dihydroxyphenylserine) has also been used, and has been investigated in the treatment of orthostatic hypotension. There is a deficit of noradrenaline as well as of dopamine in Parkinson's disease and it has been proposed that this underlies the sudden transient freezing seen usually in advanced disease. Though L-DOPS has been used in Japan and Southeast Asia already for some time, it is also currently in clinical trials at the phase III point in the United States (U.S.), Canada, Australia, and throughout Europe. Provided L-DOPS successfully completes clinical trials, it could be approved for the treatment of neurogenic orthostatic hypotension (NOH) as early as 2011. Additionally, phase II clinical trials for intradialytic hypotension are also underway. Chelsea Therapeutics obtained orphan drug status (ODS) for L-DOPS in the U.S. for NOH, and that of which associated with Parkinson's disease , pure autonomic failure, and multiple system atrophy, and is the pharmaceutical company developing it in that country.
The physiologic effect of droxidopa is by means of Increased Blood Pressure.
Droxidopa is an orally available prodrug of norepinephrine that is used in the treatment of symptomatic orthostatic hypotension due to neurogenic causes of autonomic failure. Droxidopa has had limited clinical use, but has not been linked to serum enzyme elevations nor to instances of clinically apparent acute liver injury.
A synthetic precursor of norepinephrine that is used in the treatment of PARKINSONIAN DISORDERS and ORTHOSTATIC HYPOTENSION.
See also: Norepinephrine (has active moiety).

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Drug Indication
For treatment of neurogenic orthostatic hypotension (NOH) associated with various disorders including Multiple System Atrophy, Familial Amyloid Polyneuropathy, hemodialysis induced hypotension and Parkinson's Disease. Also investigated for use/treatment in neurologic disorders, nephropathy, blood (blood forming organ disorders, unspecified), and dizzy/fainting spells.

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Mechanism of Action
Droxidopa crosses the blood-brain barrier where it is converted to norepinephrine via decarboxylation by L-aromatic-amino-acid decarboxylase. Norephinephrine acts at alpha-adrenergic receptors as a vasoconstrictor and at beta-adrenergic receptors as a heart stimulator and artery dilator.

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Pharmacodynamics
Droxidopa is an orally active synthetic precursor of norepinephrine that increases the deficient supply of norepinephrine in patients with NOH, thereby improving orthostatic blood pressure and alleviating associated symptoms of lightheadedness, dizziness, blurred vision, and syncope through the induction of tachycardia (increased heart rate) and hypertension.

C9H11NO5

213.19

213.063

C, 50.70; H, 5.20; N, 6.57; O, 37.52

23651-95-8

Droxidopa hydrochloride; 1260173-94-1; Droxidopa-13C2,15N hydrochloride; 1329556-63-9

92974

White to off-white solid powder

1.608g/cm3

549.8±50.0 °C at 760 mmHg

232-235° (dec); mp 229-232° (dec) (Ohashi)

286.3±30.1 °C

0.0±1.6 mmHg at 25°C

1.692

-0.95

5

6

3

15

235

2

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

QXWYKJLNLSIPIN-JGVFFNPUSA-N

InChI=1S/C9H11NO5/c10-7(9(14)15)8(13)4-1-2-5(11)6(12)3-4/h1-3,7-8,11-13H,10H2,(H,14,15)/t7-,8+/m0/s1

(2S,3R)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid

SM-5688; SM5688; SM 5688; Droxidopa; trade name: LDOPS; Northera; L-threodihydroxyphenylserine

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.)