Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1].

Metabolism / Metabolites
Uremic toxins often accumulate in the blood due to overeating or poor kidney filtration. Most uremic toxins are metabolic waste products that are normally excreted through urine or feces.

Toxicity Summary
Uremic toxins, such as asymmetric dimethylarginine, can be actively transported to the kidneys via organic ion transporters, particularly OAT3. Elevated uremic toxin levels can stimulate the production of reactive oxygen species (ROS). This appears to be mediated by the direct binding of uremic toxins to or inhibition of NADPH oxidases, particularly NOX4, which is abundant in the kidneys and heart (A7868). ROS can induce a variety of different DNA methyltransferases (DNMTs) involved in the silencing of the KLOTHO protein. KLOTHO has been shown to play an important role in anti-aging, mineral metabolism, and vitamin D metabolism. Multiple studies have shown that in acute or chronic kidney disease, KLOTHO mRNA and protein levels are decreased due to elevated local ROS levels (A7869).

[1]. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019;53(2):211-216.

N(ω),N(ω)-dimethyl-L-arginine is a derivative of L-arginine, with two methyl groups attached to the primary amino group of its guanidine group. It is an EC 1.14.13.39 (nitric oxide synthase) inhibitor. It is a non-protein L-α-amino acid, belonging to the guanidine group, and is a derivative of L-arginine, as well as a dimethylarginine. It is the conjugate base of N(ω),N(ω)-dimethyl-L-arginine (1+). Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical substance found in blood plasma. It is a metabolic byproduct of the ongoing protein modification process in the cytoplasm of all human cells and is closely related to the conditionally essential amino acid L-arginine. ADMA interferes with the production of nitric oxide from L-arginine, a key chemical for maintaining endothelial cell and cardiovascular health. N,N-dimethylarginine has been reported to be present in fruit flies, fission yeast, and other organisms with relevant data.
Asymmetric dimethylarginine (ADMA) is a dimethylated derivative of L-arginine, in which two methyl groups are asymmetrically linked to arginine residues. ADMA is a competitive inhibitor of NOS (nitric oxide), formed when S-adenosylmethionine protein N-methyltransferase transfers two methyl groups from S-adenosylmethionine to one of the two guanidino nitrogen atoms of the arginine residue in a protein. ADMA is released during protein degradation and is a substrate of dimethylarginine dimethylaminohydrolase (DDAH). Free ADMA in plasma competes with L-arginine for binding to heme in NOS, thereby inhibiting nitric oxide (NO) synthesis. Reduced NO synthesis inhibits vasodilation, leading to endothelial dysfunction. Elevated plasma ADMA levels can be caused by certain types of cancer, cardiovascular disease, hypertension, hyperlipidemia, type 2 diabetes, and increased oxidative stress.
Asymmetric dimethylarginine is a uremic toxin. Based on their chemical and physical properties, uremic toxins can be divided into three main categories: 1) small molecule, water-soluble, non-protein-bound compounds, such as urea; 2) small molecule, lipid-soluble and/or protein-bound compounds, such as phenols; and 3) larger so-called medium-molecule compounds, such as β2-microglobulin. Long-term exposure to uremic toxins can lead to a variety of diseases, including kidney damage, chronic kidney disease, and cardiovascular disease. Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical substance found in blood plasma. It is a metabolic byproduct of a continuous protein modification process in the cytoplasm of all human cells. It is closely related to the conditionally essential amino acid L-arginine. ADMA interferes with the formation of nitric oxide from L-arginine, a key chemical substance for maintaining endothelial cell and cardiovascular health. Asymmetric dimethylarginine is produced during protein methylation, a common post-translational modification mechanism of proteins. This reaction is catalyzed by a group of enzymes called S-adenosylmethionine protein N-methyltransferases (protein methyltransferases I and II). The methyl group used to generate ADMA is derived from the methyl donor S-adenosylmethionine, an intermediate in homocysteine metabolism. (Homocysteine is an important blood chemical as it is also a marker of cardiovascular disease). After synthesis, ADMA migrates into the extracellular space and then enters the plasma. Asymmetric dimethylarginine was determined using high-performance liquid chromatography. Dimethyl-L-arginine is a metabolite found or produced in Saccharomyces cerevisiae. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor formed by the methylation of arginine residues in proteins and released upon proteolysis. In this reaction, S-adenosylmethionine is the methyl donor, and S-adenosylhomocysteine is the demethylation product. Therefore, ADMA and homocysteine are biochemically related. Both plasma homocysteine and ADMA concentrations are elevated in patients with renal insufficiency, likely due to impaired metabolic clearance (rather than urinary clearance). Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease in patients with end-stage renal disease, particularly in those without malnutrition and inflammation. Furthermore, plasma ADMA levels are associated with cardiovascular disease in patients with renal failure. Both homocysteine and ADMA are believed to exert their adverse vascular effects by impairing endothelial cell-dependent nitric oxide function, leading to decreased vasodilation, increased smooth muscle cell proliferation, platelet dysfunction, and increased monocyte adhesion.

C8H14D6CL2N4O2

281.21

280.134

1313730-20-9

Asymmetric dimethylarginine;30315-93-6;Asymmetric dimethylarginine dihydrochloride;220805-22-1

123831

White to off-white solid powder

195 - 197 °C

-3.6

3

4

6

14

215

1

CN(C)C(=NCCC[C@@H](C(=O)O)N)N

YDGMGEXADBMOMJ-LURJTMIESA-N

InChI=1S/C8H18N4O2/c1-12(2)8(10)11-5-3-4-6(9)7(13)14/h6H,3-5,9H2,1-2H3,(H2,10,11)(H,13,14)/t6-/m0/s1

(2S)-2-amino-5-[[amino(dimethylamino)methylidene]amino]pentanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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.)