Identification

Name
Tiopronin
Accession Number
DB06823
Type
Small Molecule
Groups
Approved, Investigational
Description

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.

Structure
Thumb
Synonyms
  • alpha-mercaptopropionylglycine
  • alpha-MPG
  • Tiopronine
  • α-MPG
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ThiolaTablet, sugar coated100 mg/1OralMission Pharmacal1988-08-11Not applicableUs
International/Other Brands
Acadione (Sanofi-Aventis France) / Capen / Captimer (MIT Gesundheit) / Epatiol (Medici Italy) / Kai Na / Kai Xi Lai / Mucosyt (Bioprogress) / Stargen (Shyh Dar) / Sutilan / Vincol
Categories
UNII
C5W04GO61S
CAS number
1953-02-2
Weight
Average: 163.19
Monoisotopic: 163.030314328
Chemical Formula
C5H9NO3S
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-[(1-hydroxy-2-sulfanylpropylidene)amino]acetic acid
SMILES
CC(S)C(O)=NCC(O)=O

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.

Associated Conditions
Pharmacodynamics
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.

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.

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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Tiopronin which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Tiopronin which could result in a higher serum level.
AlprazolamAlprazolam may decrease the excretion rate of Tiopronin which could result in a higher serum level.
AmilorideAmiloride may increase the excretion rate of Tiopronin which could result in a lower serum level and potentially a reduction in efficacy.
AmitriptylineTiopronin may decrease the excretion rate of Amitriptyline which could result in a higher serum level.
AmlodipineAmlodipine may decrease the excretion rate of Tiopronin which could result in a higher serum level.
AmoxicillinAmoxicillin may decrease the excretion rate of Tiopronin which could result in a higher serum level.
AmphetamineAmphetamine may decrease the excretion rate of Tiopronin which could result in a higher serum level.
AmpicillinAmpicillin may decrease the excretion rate of Tiopronin which could result in a higher serum level.
AuranofinAuranofin may decrease the excretion rate of Tiopronin which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:24857648]
  2. 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. [PubMed:8569983]
  3. 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. [PubMed:7836789]
  4. Carlsson MS, Denneberg T, Emanuelsson BM, Kagedal B, Lindgren S: Pharmacokinetics of oral tiopronin. Eur J Clin Pharmacol. 1993;45(1):79-84. [PubMed:8405034]
  5. 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. [PubMed:1505618]
  6. 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. [PubMed:3534301]
  7. 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. [PubMed:20559104]
  8. 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. [PubMed:15865542]
  9. Remien A, Kallistratos G, Burchardt P: Treatment of cystinuria with Thiola (alpha-mercaptopropionyl glycine). Eur Urol. 1975;1(5):227-8. [PubMed:1233187]
  10. 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. [PubMed:25026975]
  11. 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. [PubMed:11494716]
External Links
KEGG Drug
D01430
KEGG Compound
C12876
PubChem Compound
5483
PubChem Substance
347827801
ChemSpider
5283
BindingDB
50020805
ChEBI
32229
ChEMBL
CHEMBL1314
Drugs.com
Drugs.com Drug Page
Wikipedia
Tiopronin
ATC Codes
R05CB12 — Tiopronin
MSDS
Download (27.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentAneurysmal Subarachnoid Hemorrhage1
2CompletedTreatmentDrug-Induced Liver Injury1
2Not Yet RecruitingTreatmentCystine renal calculi1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, sugar coatedOral100 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.71 mg/mLALOGPS
logP0.08ALOGPS
logP0.29ChemAxon
logS-1.8ALOGPS
pKa (Strongest Acidic)3.84ChemAxon
pKa (Strongest Basic)1.32ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area69.89 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity38.29 m3·mol-1ChemAxon
Polarizability15.59 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
N-acyl-alpha-amino acid / Carboxamide group / Secondary carboxylic acid amide / Alkylthiol / Carboxylic acid / Monocarboxylic acid or derivatives / Organic nitrogen compound / Organosulfur compound / Organooxygen compound / Organonitrogen compound
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
N-acyl-amino acid (CHEBI:32229)

Enzymes

Kind
Protein
Organism
Human
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
  1. 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. [PubMed:2998407]

Drug created on September 14, 2010 10:21 / Updated on August 02, 2018 05:40