Identification
- Summary
Tiopronin is a thiol agent indicated for the prevention of kidney stone formation in patients with severe homozygous cystinuria.
- Brand Names
- Thiola
- Generic Name
- Tiopronin
- DrugBank Accession Number
- DB06823
- 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.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Tiopronin (DB06823)
- Weight
- Average: 163.19
Monoisotopic: 163.030314328 - Chemical Formula
- C5H9NO3S
- Synonyms
- Tiopronin
- Tiopronine
- Tiopronino
- Tioproninum
Pharmacology
- Indication
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.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Prevention of Kidney stone formation •••••••••••• - Contraindications & Blackbox Warnings
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Not Available
- Mechanism of action
Kidney stones form when the solubility limit is exceeded and urine becomes supersaturated with endogenous cystine. Tiopronin is an active reducing agent which undergoes a thiol-disulfide exchange with cystine to form a water-soluble mixed disulfide complex. Thus, the amount of sparingly soluble cystine is reduced. By reducing urinary cystine concentrations below the solubility limit, tiopronin helps reduce cystine stone formation.
- 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.
- Volume of distribution
The volume of distribution of tiopronin is high at 455 L, indicating that a large portion of the drug is bound to tissues outside plasma.
- Protein binding
Tiopronin undergoes extensive protein binding in plasma. It is thought that this occurs through the formation of a disulphide bridge to the free thiol group of albumin.
- 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.
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- Route of elimination
Tiopronin is 100% excreted in urine.
- Half-life
Tiopronin has a long terminal half life of 53 hours in healthy subjects. However, the unbound drug fraction of tiopronin is eliminated much more rapidly from plasma with a calculated half life of 1.8 hours.
- Clearance
Total renal clearance for the total and unbound fractions of tiopronin were found to be 3.3 and 13.3 L/h respectively.
- Adverse Effects
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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.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Abacavir may decrease the excretion rate of Tiopronin which could result in a higher serum level. Aceclofenac Aceclofenac may decrease the excretion rate of Tiopronin which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Tiopronin which could result in a higher serum level. Acetaminophen Acetaminophen may decrease the excretion rate of Tiopronin which could result in a higher serum level. Acetazolamide Acetazolamide may increase the excretion rate of Tiopronin which could result in a lower serum level and potentially a reduction in efficacy. - Food Interactions
- Take at the same time every day. Take each dose at the same time every day.
- Take on an empty stomach. Take tiopronin at least 1 hour before or 2 hours after eating food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- International/Other Brands
- Acadione (Sanofi-Aventis France) / Capen / Captimer (MIT Gesundheit) / Epatiol (Medici Italy) / Kai Na / Mucosyt (Bioprogress) / Sutilan / Thiola / Vincol
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Thiola Tablet, sugar coated 100 mg/1 Oral Mission Pharmacal Company 1988-08-11 Not applicable US 
Thiola EC Tablet, delayed release 300 mg/1 Oral Mission Pharmacal Company 2019-06-28 Not applicable US Thiola EC Tablet, delayed release 100 mg/1 Oral Mission Pharmacal Company 2019-06-28 Not applicable US - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tiopronin Tablet, delayed release 300 mg/1 Oral Amneal Pharmaceuticals NY LLC 2023-08-16 Not applicable US Tiopronin Tablet, delayed release 300 mg/1 Oral Torrent Pharmaceuticals Limited 2024-01-30 Not applicable US Tiopronin Tablet, sugar coated 100 mg/1 Oral Teva Pharmaceuticals USA, Inc. 2021-05-17 Not applicable US Tiopronin Tablet, delayed release 100 mg/1 Oral Torrent Pharmaceuticals Limited 2024-01-30 Not applicable US
Categories
- ATC Codes
- G04BX16 — Tiopronin
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as n-acyl-alpha amino acids. These are compounds containing an alpha amino acid which bears an acyl group at its terminal nitrogen atom.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- N-acyl-alpha amino acids
- Alternative Parents
- Secondary carboxylic acid amides / Monocarboxylic acids and derivatives / Carboxylic acids / Alkylthiols / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
- Substituents
- Aliphatic acyclic compound / Alkylthiol / Carbonyl group / Carboxamide group / Carboxylic acid / Hydrocarbon derivative / Monocarboxylic acid or derivatives / N-acyl-alpha-amino acid / Organic nitrogen compound / Organic oxide
- Molecular Framework
- Aliphatic acyclic compounds
- External Descriptors
- N-acyl-amino acid (CHEBI:32229)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- C5W04GO61S
- CAS number
- 1953-02-2
- InChI Key
- YTGJWQPHMWSCST-UHFFFAOYSA-N
- InChI
- InChI=1S/C5H9NO3S/c1-3(10)5(9)6-2-4(7)8/h3,10H,2H2,1H3,(H,6,9)(H,7,8)
- IUPAC Name
- 2-(2-sulfanylpropanamido)acetic acid
- SMILES
- CC(S)C(=O)NCC(O)=O
References
- General References
- Pearle MS, Goldfarb DS, Assimos DG, Curhan G, Denu-Ciocca CJ, Matlaga BR, Monga M, Penniston KL, Preminger GM, Turk TM, White JR: Medical management of kidney stones: AUA guideline. J Urol. 2014 Aug;192(2):316-24. doi: 10.1016/j.juro.2014.05.006. Epub 2014 May 20. [Article]
- Lindell A, Denneberg T, Jeppsson JO: Urinary excretion of free cystine and the tiopronin-cysteine-mixed disulfide during long term tiopronin treatment of cystinuria. Nephron. 1995;71(3):328-42. [Article]
- Giannakopoulos X, Kalfakakou V, Tsoumanis P, Karkabounas S, Giannakis D, Chambilomatis P, Evangelou A, Kallistratos G: [Results of treatment of cystinuria and cystine lithiasis with alpha-mercaptopropionylglycine. Apropos of 40 patients]. J Urol (Paris). 1994;100(3):129-34. [Article]
- Carlsson MS, Denneberg T, Emanuelsson BM, Kagedal B, Lindgren S: Pharmacokinetics of oral tiopronin. Eur J Clin Pharmacol. 1993;45(1):79-84. [Article]
- Hercelin B, Leroy P, Nicolas A, Gavriloff C, Chassard D, Thebault JJ, Reveillaud MT, Salles MF, Netter P: The pharmacokinetics of tiopronin and its principal metabolite (2-mercaptopropionic acid) after oral administration to healthy volunteers. Eur J Clin Pharmacol. 1992;43(1):93-5. [Article]
- Pak CY, Fuller C, Sakhaee K, Zerwekh JE, Adams BV: Management of cystine nephrolithiasis with alpha-mercaptopropionylglycine. J Urol. 1986 Nov;136(5):1003-8. [Article]
- Kim GH, Kellner CP, Hickman ZL, Zacharia BE, Starke RM, Hwang BY, Ducruet AF, Fernandez L, Mayer SA, Tracey KJ, Connolly ES Jr: A phase I clinical trial of tiopronin, a putative neuroprotective agent, in aneurysmal subarachnoid hemorrhage. Neurosurgery. 2010 Jul;67(1):182-5; discussion 186. doi: 10.1227/01.NEU.0000370919.93259.3C. [Article]
- Dolin DJ, Asplin JR, Flagel L, Grasso M, Goldfarb DS: Effect of cystine-binding thiol drugs on urinary cystine capacity in patients with cystinuria. J Endourol. 2005 Apr;19(3):429-32. [Article]
- Remien A, Kallistratos G, Burchardt P: Treatment of cystinuria with Thiola (alpha-mercaptopropionyl glycine). Eur Urol. 1975;1(5):227-8. [Article]
- Zheng Z, Xue Y, Jia J, Wei L, Shang W, Lin S: Tiopronin-induced membranous nephropathy: a case report. Ren Fail. 2014 Oct;36(9):1455-60. doi: 10.3109/0886022X.2014.926754. Epub 2014 Jul 16. [Article]
- Alvarez Navascues R, Vidau Arguelles P, Rodriguez Suarez C, Herrera Perez de Villar J, Suarez Heiva M: [Nephrotic syndrome and anasarca status, secondary to treatment with tiopronin in a case of cystinuria]. Arch Esp Urol. 2001 Jun;54(5):438-40. [Article]
- External Links
- MSDS
- Download (27.4 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Treatment Cystinuria 1 2 Completed Treatment Aneurysmal Subarachnoid Hemorrhage (A-sah) 1 2 Completed Treatment Cystinuria 1 2 Completed Treatment Drug Induced Liver Injury 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Granule Granule 600 MG Suppository Suppository 100 MG Suppository 200 MG Suppository 50 MG Suppository 600 MG Tablet Tablet 600 MG Tablet, sugar coated Oral 100 mg/1 Tablet, delayed release Oral 100 mg/1 Tablet, delayed release Oral 300 mg/1 Spray - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US11458104 No 2018-11-14 2038-11-14 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source logP -0.53 Chemaxon pKa (Strongest Acidic) 3.86 Chemaxon pKa (Strongest Basic) -4.2 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 66.4 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 37.77 m3·mol-1 Chemaxon Polarizability 15.31 Å3 Chemaxon Number of Rings 0 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-03xr-9600000000-336996d138a3518dea07 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-000i-9000000000-9032ff406775eec3b316 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-9000000000-6c478ab00cdab89e428d Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-03di-9100000000-0f4384e80e6e5a68ac7f Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0bu0-9000000000-b56441bbb4dbdbda5855 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-01q9-9000000000-411844bc2fc275b9ba30 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 126.81232 predictedDeepCCS 1.0 (2019) [M+H]+ 130.28636 predictedDeepCCS 1.0 (2019) [M+Na]+ 138.85399 predictedDeepCCS 1.0 (2019)
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Peroxidase activity
- Specific Function
- Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production o...
- Gene Name
- MPO
- Uniprot ID
- P05164
- Uniprot Name
- Myeloperoxidase
- Molecular Weight
- 83867.71 Da
References
- Cuperus RA, Muijsers AO, Wever R: Antiarthritic drugs containing thiol groups scavenge hypochlorite and inhibit its formation by myeloperoxidase from human leukocytes. A therapeutic mechanism of these drugs in rheumatoid arthritis? Arthritis Rheum. 1985 Nov;28(11):1228-33. [Article]
Drug created at September 14, 2010 16:21 / Updated at February 21, 2021 18:52