Increasing dosages of ascorbic acid, but not the enzyme's cofactor 2-oxoglutarate, decreased the inhibitory impact of tiopronin (NMPG) on HPH-2 in an in vitro Von Hippel-Lindau protein binding experiment [2].

Myeloperoxidase activity is successfully decreased and colon damage is attenuated by tiopronin (NMPG). Moreover, in the inflammatory colon, NMPG dramatically reduced the expression of proinflammatory mediators. In human colon cancer cells, NMPG stimulates the production of hypoxia-inducible factor-1α (HIF-1α), which increases the secretion of vascular endothelial growth factor (VEGF). VEGF is a target of HIF-1 and is implicated in the healing of gastrointestinal mucosal ulcers. genetic material. By blocking HIF prolyl hydroxylase-2 (HPH-2), an enzyme that is crucial in adversely controlling the stability of the HIF-1α protein, NMPG causes the appearance of HIF-1α [2].

Absorption, Distribution and Excretion
Tiopronin is absorbed slowly, reaching peak plasma concentrations 3-6 hours after oral administration. A study in healthy subjects found that the bioavailability of total Tiopronin and free Tiopronin was 63% and 40%, respectively. Tiopronin is 100% excreted in the urine. The volume of distribution of Tiopronin is as high as 455 liters, indicating that most of the drug binds to tissues outside of plasma. The renal clearance of total Tiopronin and free Tiopronin is 3.3 L/h and 13.3 L/h, respectively. Metabolism/Metabolites The major metabolite of Tiopronin is 2-mercaptopropionic acid (2-MPA). 10-15% of the drug is metabolized to 2-MPA via hydrolysis. Biological Half-Life In healthy subjects, Tiopronin has a relatively long terminal half-life of 53 hours. However, the free Tiopronin drug fraction is cleared from the plasma much faster, with a calculated half-life of 1.8 hours.

Protein Binding
Tiopronin binds extensively to proteins in plasma. This is believed to occur through the formation of disulfide bonds with free sulfhydryl groups in albumin.

[1]. Detection of tiopronin in body fluids and pharmaceutical products using red-emissive DNA-stabilized silver nanoclusters as a fluorescent probe. Mikrochim Acta. 2019 Aug 8;186(9):609.

[2]. N-(2-Mercaptopropionyl)-glycine, a diffusible antioxidant, activates HIF-1 by inhibiting HIF prolyl hydroxylase-2: implication in amelioration of rat colitis by the antioxidant. Biochem Biophys Res Commun. 2014 Jan 17;443(3):1008-13.

Tiopronin is an N-acyl amino acid. It is a prescription thiol drug primarily used to treat severe homozygous cystinuria. Patients with cystinuria have high cystine levels in their urine, increasing the risk of kidney stones. Tiopronin is used as a second-line treatment to control cystine precipitation and excretion, and to prevent kidney stone formation. It is used after first-line non-pharmacological treatments (including increasing fluid intake, restricting sodium and protein intake, and alkalinizing urine) have failed. Because cystinuria is a relatively rare disease, Tiopronin is classified as an orphan drug and is not patented in the United States. Its uses and efficacy are similar to D-penicillamine, but it has the advantage of far fewer adverse reactions. The dosage of Tiopronin needs to be determined on an individual basis, with close monitoring of urinary cystine concentration and urine volume. Tiopronin can also be used to treat Wilson's disease (a disease of copper overload in the body), which can cause metal nanoparticles to bind. Tiopronin has been investigated for the treatment of arthritis and as a neuroprotective agent for aneurysmal subarachnoid hemorrhage.
Tiopronin is a reducing and complexing thiol. Its mechanism of action is the reduction of cystine disulfide bonds.
Tiopronin is an acylated thiol derivative of glycine, possessing reducing and complexing properties. Tiopronin cleaves the disulfide bonds of cystine and combines with the thiol group of the resulting cysteine monomer to form a soluble Tiopronin-cysteine mixed disulfide bond. This mixed disulfide bond is more soluble in water than cystine and is therefore more easily excreted. This leads to a decrease in urinary cystine concentration, thereby reducing the formation of cystine stones.
Thiol-acylated derivative of glycine.
Pharmaceutical Indications

Tiopronin is indicated for the prevention of kidney stone formation in patients with severe homozygous cystinuria, whose urinary cystine concentration is greater than 500 mg/day, and who have not responded to non-pharmacological treatments (such as increasing fluid intake, reducing sodium and protein intake, and alkalinizing urine).

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Mechanism of Action
When the solubility exceeds the limit, and endogenous cystine in the urine becomes supersaturated, kidney stones form. Tiopronin is an active reducing agent that undergoes a thiol-disulfide bond exchange with cystine, forming a water-soluble mixed disulfide bond complex. Therefore, the amount of poorly soluble cystine is reduced. Tiopronin helps reduce the formation of cystine stones by lowering the concentration of cystine in the urine below the solubility limit.

C5H9NO3S

163.1949

163.03

1953-02-2

Tiopronin-13C,d3;1189695-13-3;Tiopronin-d3;1189700-74-0

5483

White to off-white solid powder

1.3±0.1 g/cm3

418.3±30.0 °C at 760 mmHg

93-98 °C

206.8±24.6 °C

0.0±2.1 mmHg at 25°C

1.519

-0.33

3

4

3

10

148

0

YTGJWQPHMWSCST-UHFFFAOYSA-N

InChI=1S/C5H9NO3S/c1-3(10)5(9)6-2-4(7)8/h3,10H,2H2,1H3,(H,6,9)(H,7,8)

2-(2-sulfanylpropanoylamino)acetic acid

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)

H2O : ~100 mg/mL (~612.78 mM)
DMSO : ≥ 100 mg/mL (~612.78 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (15.32 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 (15.32 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 (15.32 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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Solubility in Formulation 4: 130 mg/mL (796.62 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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