Tiopronin

Absorption

Tiopronin undergoes slow absorption, reaching peak plasma concentration 3-6 hours after ingestion. In a study of healthy subjects, the bioavailability of total and unbound tiopronin was found to be 63% and 40%, respectively.

Toxicity

Long-term carcinogenicity and mutagenicity studies have not been performed with tiopronin. In experimental animal studies, high doses of tiopronin were shown to interfere with the maintenance of pregnancy and viability of a fetus. No neural tube defects were detected when tiopronin was given to mice and rats in doses up to 10 times the highest recommended human dose. However, the manufacturer does not rule out the possibility of teratogenicity, as it has been seen with the drug d-penicillamine, which acts with a similar mechanism to tiopronin. Tiopronin is not recommended for use in breastfeeding mothers and has no established safety in children 9 years old or younger. There have been case reports of tiopronin-related nephropathy.

Description

Tiopronin is a sulfiydryl derivative of N-propylglycine useful in the treatment of cystine urolithiasis in children. It is also reportedly effective in the management of rheumatoid polyarthritis, possibly due to its inhibitory effect on the free oxygen radicals produced by inflammatory macrophages and granulocytes.

Description

Tiopronin is an antioxidant that has diverse biological activities. It reduces free radical production by murine macrophages and granulocytes in vitro in a dose-dependent manner. Tiopronin induces expression of hypoxia-inducible factor 1α (HIF-1α) and increases VEGF secretion in human colon carcinoma cells. Rectal administration (500 μL of a 10 mM solution) reduces myeloperoxidase activity and reduces pro-inflammatory cytokine production in the colon in a rat model of colitis. Tiopronin (80-320 mg/kg per day) reduces the incidence of cleft palate in fetuses born to female mice orally exposed to teratogenic methylmercury chloride. Tiopronin (100 mg/kg) reduces heme oxygenase 1 mRNA expression, lipid peroxidation, and transverse aortic constriction in a mouse model of cardiac hypertrophy. Tiopronin (20 mg/kg) is hepatoprotective, increasing activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase and reversing hepatocyte degeneration in a rat model of high-fat diet-induced non-alcoholic steatohepatitis.

Chemical properties

White Solid

Originator

Roussel-Uclaf (Japan)

The Uses of Tiopronin

N-(2-Mercaptopropionyl)glycine or Tiopronin has been used:

• in the preparation of polyethylenimine (PEI)-coated gold microparticles (PEI-gold) for biolistic delivery of nucleic acids
• to study the role of reactive oxygen species (ROS) at the reperfusion stage in in vivo isoflurane preconditioning-induced neuroprotection
• as a ROS inhibitor to study its effect on lysophosphatidylcholine (LPC)-induced inflammasome activation

The Uses of Tiopronin

It is used as antidote against heavy metal poisoning; hepatoprotectant; mucolytic.

Indications

Tiopronin is indicated for the prevention of kidney stone formation in patients with severe homozygous cystinuria consisting of a urinary cystine concentration greater than 500 mg/day, and who have failed treatment with non-pharmacological measures of increased fluid intake, decreased sodium and protein intake, and urine alkalinization.

Background

Tiopronin is a prescription thiol drug used primarily in the treatment of severe homozygous cystinuria. Patients with cystinuria excrete high levels of cystine in their urine and are at risk for kidney stone formation. Tiopronin is used as a second-line therapy to control the rate of cystine precipitation and excretion, and prevent kidney stone formation. It is used after a failure of the non-pharmacological first line treatment consisting of increased fluid intake, restriction of sodium and protein, and urinary alkalinization. As cystinuria is a relatively rare disease, tiopronin is classified as an orphan drug and is not patented in the United States. It is similar to d-penicillamine in use and efficacy, but offers the advantage of far less adverse effects. Tiopronin is dosed on an individual basis using close monitoring of urinary cystine concentrations and urinary output.
Tiopronin may also be used to bind metal nanoparticles in Wilson's disease, which is an overload of copper in the body. It has been investigated for use in the treatment of arthritis and as a neuroprotective agent in aneurysmal subarachnoid hemorrhage.

What are the applications of Application

Tiopronin is controls the rate of cystine precipitation and excretion

Definition

ChEBI: Tiopronin is a N-acyl-amino acid.

Manufacturing Process

α-Benzylmercaptopropionic acid (melting point 76°C to 78°C; 100 g) prepared by condensation of α-mercaptopropionic acid with benzyl chloride is allowed to stand overnight with 80 g of thionyl chloride. After removal of excess thionyl chloride distillation in vacuo gives 70 g of α-benzylmercaptopropionic acid chloride of boiling point 138°C to 139°C/7 to 8 mm Hg.
Then, 25 g of glycine is dissolved in 165 ml of 2 N sodium hydroxide solution and 70 g of α-benzylmercaptopropionic acid chloride and 100 ml of 2 N sodium hydroxide solution are dropped thereinto simultaneously at 3°C to 5°C. The solution is then stirred at room temperature for 3 to 4 hours to complete the reaction, the reaction solution is washed with ether, the aqueous layer is acidified with hydrochloric acid, and the resulting crystals are collected by filtration. These are recrystallized from a mixture of methanol and ethyl acetate to give 60 g of α-benzylmercaptopropionylglycine of melting point 133°C to 134°C.
This α-benzylmercaptopropionylglycine (60 g) is dissolved in 400 ml of liquid ammonia, kept at about -50°C, and 12 g of sodium metal is gradually added thereto. After the reaction, excess ammonia is removed therefrom, the residue is dissolved in water, washed with ether and the residual aqueous layer is adjusted to pH 1 with hydrochloric acid and concentrated in vacuo in a stream of hydrogen sulfide. The crystalline residue is dried and recrystallized from ethyl acetate to give 25 g of α-mercaptopropionylglycine of melting point 95°C to 97°C.

brand name

Thiola

Therapeutic Function

Antidote (heavy metal)

Biochem/physiol Actions

N-(2-Mercaptopropionyl)glycine (NMPG) is a thiol compound associated with autoimmune hypoglycemia. It is a diffusible antioxidant and reduces the severity of colonic injury. NMPG also relieves myeloperoxidase activity and stimulates hypoxia-inducible factor-1 (HIF-1) - vascular endothelial growth factor (VEGF) pathway for ulcer healing.

Veterinary Drugs and Treatments

Tiopronin is indicated for the prevention of cystine urolithiasis in patients where dietary therapy combined with urinary alkalinization is not completely effective. It may also be useful in combination with urine alkalinization to dissolve stones.

Metabolism

The principle metabolite of tiopronin is 2-mercaptopropionic acid (2-MPA). Between 10-15% of the drug is metabolized to 2-MPA via hydrolysis.