Identification

Name
Penicillamine
Accession Number
DB00859  (APRD01171)
Type
Small Molecule
Groups
Approved
Description

Penicillamine is a pharmaceutical of the chelator class. The pharmaceutical form is D-penicillamine, as L-penicillamine is toxic (it inhibits the action of pyridoxine). It is an α-amino acid metabolite of penicillin, although it has no antibiotic properties.

Structure
Thumb
Synonyms
  • (−)-penicillamine
  • (S)-2-amino-3-mercapto-3-methylbutanoic acid
  • (S)-3,3-dimethylcysteine
  • 3-mercapto-D-valine
  • D-(−)-penicillamine
  • D-penicillamine
  • D-β,β-dimethylcysteine
External IDs
NSC-81549
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CuprimineCapsule250 mg/1OralAton Pharma, Inc.1970-12-04Not applicableUs
CuprimineCapsule250 mgOralValeant Canada Lp Valeant Canada S.E.C.1964-12-31Not applicableCanada
CuprimineCapsule125 mgOralMerck Ltd.1980-12-312005-06-18Canada
DepenTablet250 mg/1OralMeda Pharmaceuticals Ltd1978-11-30Not applicableUs
Depen Tab 250mgTablet250 mgOralCarter Horner Corp.1981-12-312003-08-19Canada
International/Other Brands
Atamir (Sandoz)
Categories
UNII
GNN1DV99GX
CAS number
52-67-5
Weight
Average: 149.211
Monoisotopic: 149.051049291
Chemical Formula
C5H11NO2S
InChI Key
VVNCNSJFMMFHPL-VKHMYHEASA-N
InChI
InChI=1S/C5H11NO2S/c1-5(2,9)3(6)4(7)8/h3,9H,6H2,1-2H3,(H,7,8)/t3-/m0/s1
IUPAC Name
(2S)-2-amino-3-methyl-3-sulfanylbutanoic acid
SMILES
[H][[email protected]](N)(C(O)=O)C(C)(C)S

Pharmacology

Indication

For treatment of Wilson's disease, cystinuria and active rheumatoid arthritis.

Structured Indications
Pharmacodynamics

Penicillamine is a chelating agent used in the treatment of Wilson's disease. It is also used to reduce cystine excretion in cystinuria and to treat patients with severe, active rheumatoid arthritis unresponsive to conventional therapy. Penicillamine is used as a form of immunosuppression to treat rheumatoid arthritis. It works by reducing numbers of T-lymphocytes, inhibiting macrophage function, decreasing IL-1, decreasing rheumatoid factor, and preventing collagen from cross-linking. Its use in Wilson's disease, a rare genetic disorder of copper metabolism, relies on its binding to accumulated copper and elimination through urine.

Mechanism of action

Penicillamine is a chelating agent recommended for the removal of excess copper in patients with Wilson's disease. From in vitro studies which indicate that one atom of copper combines with two molecules of penicillamine. Penicillamine also reduces excess cystine excretion in cystinuria. This is done, at least in part, by disulfide interchange between penicillamine and cystine, resulting in formation of penicillamine-cysteine disulfide, a substance that is much more soluble than cystine and is excreted readily. Penicillamine interferes with the formation of cross-links between tropocollagen molecules and cleaves them when newly formed. The mechanism of action of penicillamine in rheumatoid arthritis is unknown although it appears to suppress disease activity. Unlike cytotoxic immunosuppressants, penicillamine markedly lowers IgM rheumatoid factor but produces no significant depression in absolute levels of serum immunoglobulins. Also unlike cytotoxic immunosuppressants which act on both, penicillamine in vitro depresses T-cell activity but not B-cell activity.

TargetActionsOrganism
ACopper
chelator
Human
Absorption

rapidly but incompletely

Volume of distribution
Not Available
Protein binding

>80% (bound to plasma proteins)

Metabolism

Hepatic

Route of elimination

Excretion is mainly renal, mainly as disulfides.

Half life

1 hour

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

Interactions

Drug Interactions
DrugInteractionDrug group
AlgeldrateThe serum concentration of Penicillamine can be decreased when it is combined with Algeldrate.Approved, Experimental
AlmagateThe serum concentration of Penicillamine can be decreased when it is combined with Almagate.Experimental
AlmasilateThe serum concentration of Penicillamine can be decreased when it is combined with Almasilate.Approved, Experimental
AloglutamolThe serum concentration of Penicillamine can be decreased when it is combined with Aloglutamol.Experimental
AluminiumThe serum concentration of Penicillamine can be decreased when it is combined with Aluminium.Approved
Aluminium acetoacetateThe serum concentration of Penicillamine can be decreased when it is combined with Aluminium acetoacetate.Experimental
Aluminium glycinateThe serum concentration of Penicillamine can be decreased when it is combined with Aluminium glycinate.Experimental
Aluminum hydroxideThe serum concentration of Penicillamine can be decreased when it is combined with Aluminum hydroxide.Approved
Bismuth SubcitrateThe serum concentration of Penicillamine can be decreased when it is combined with Bismuth Subcitrate.Approved
Bismuth subnitrateThe serum concentration of Penicillamine can be decreased when it is combined with Bismuth subnitrate.Experimental
Calcium CarbonateThe serum concentration of Penicillamine can be decreased when it is combined with Calcium Carbonate.Approved
Calcium silicateThe serum concentration of Penicillamine can be decreased when it is combined with Calcium silicate.Experimental
DigoxinThe serum concentration of Digoxin can be decreased when it is combined with Penicillamine.Approved
EltrombopagThe serum concentration of Penicillamine can be increased when it is combined with Eltrombopag.Approved
Ferric CarboxymaltoseFerric Carboxymaltose can cause a decrease in the absorption of Penicillamine resulting in a reduced serum concentration and potentially a decrease in efficacy.Approved
Ferric CitrateFerric Citrate can cause a decrease in the absorption of Penicillamine resulting in a reduced serum concentration and potentially a decrease in efficacy.Approved, Investigational
Ferric pyrophosphateFerric pyrophosphate can cause a decrease in the absorption of Penicillamine resulting in a reduced serum concentration and potentially a decrease in efficacy.Approved
HydrotalciteThe serum concentration of Penicillamine can be decreased when it is combined with Hydrotalcite.Experimental, Investigational
IronIron can cause a decrease in the absorption of Penicillamine resulting in a reduced serum concentration and potentially a decrease in efficacy.Approved
Iron DextranIron Dextran can cause a decrease in the absorption of Penicillamine resulting in a reduced serum concentration and potentially a decrease in efficacy.Approved, Vet Approved
Iron saccharateIron saccharate can cause a decrease in the absorption of Penicillamine resulting in a reduced serum concentration and potentially a decrease in efficacy.Approved
MagaldrateThe serum concentration of Penicillamine can be decreased when it is combined with Magaldrate.Approved, Withdrawn
Magnesium HydroxideThe serum concentration of Penicillamine can be decreased when it is combined with Magnesium Hydroxide.Approved
Magnesium oxideThe serum concentration of Penicillamine can be decreased when it is combined with Magnesium oxide.Approved
Magnesium peroxideThe serum concentration of Penicillamine can be decreased when it is combined with Magnesium peroxide.Experimental
Magnesium silicateThe serum concentration of Penicillamine can be decreased when it is combined with Magnesium silicate.Approved, Experimental
Magnesium TrisilicateThe serum concentration of Penicillamine can be decreased when it is combined with Magnesium Trisilicate.Approved
PolaprezincThe serum concentration of Penicillamine can be decreased when it is combined with Polaprezinc.Approved, Investigational
Sodium bicarbonateThe serum concentration of Penicillamine can be decreased when it is combined with Sodium bicarbonate.Approved
TeriflunomideThe serum concentration of Penicillamine can be increased when it is combined with Teriflunomide.Approved
TromethamineThe serum concentration of Penicillamine can be decreased when it is combined with Tromethamine.Approved
Food Interactions
  • Drink liberally.
  • Food reduces availability, take on an empty stomach.

References

Synthesis Reference

Manfred Klaus Joachim Bock, deceased, "Method of producing penicillamine." U.S. Patent US3968154, issued November, 1960.

US3968154
General References
  1. WALSHE JM: Penicillamine, a new oral therapy for Wilson's disease. Am J Med. 1956 Oct;21(4):487-95. [PubMed:13362281]
  2. Walshe JM: The story of penicillamine: a difficult birth. Mov Disord. 2003 Aug;18(8):853-9. [PubMed:12889074]
  3. Gong Y, Frederiksen SL, Gluud C: D-penicillamine for primary biliary cirrhosis. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004789. [PubMed:15495127]
  4. Suarez-Almazor ME, Spooner C, Belseck E: Penicillamine for rheumatoid arthritis. Cochrane Database Syst Rev. 2000;(2):CD001460. [PubMed:10796440]
  5. Munro R, Capell HA: Penicillamine. Br J Rheumatol. 1997 Jan;36(1):104-9. [PubMed:9117147]
External Links
KEGG Drug
D00496
KEGG Compound
C07418
PubChem Compound
5852
PubChem Substance
46508305
ChemSpider
5643
BindingDB
50217941
ChEBI
7959
ChEMBL
CHEMBL1430
Therapeutic Targets Database
DNC000575
PharmGKB
PA450840
HET
LEI
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Penicillamine
ATC Codes
M01CC01 — Penicillamine
AHFS Codes
  • 64:00.00 — Heavy Metal Antagonists
PDB Entries
3h5g
FDA label
Download (264 KB)
MSDS
Download (71.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentBrain and Central Nervous System Tumors1
2RecruitingTreatmentArteriovenous fistula occlusion1
Not AvailableNo Longer AvailableNot AvailableScleroderma1

Pharmacoeconomics

Manufacturers
  • Aton pharma inc
  • Meda pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
CapsuleOral125 mg
CapsuleOral250 mg/1
CapsuleOral250 mg
TabletOral250 mg/1
TabletOral250 mg
Prices
Unit descriptionCostUnit
Penicillamine(d-) powder8.88USD g
Cuprimine 250 mg capsule5.63USD capsule
Depen 250 mg titratab4.73USD tablet
Penicillamine powder2.81USD g
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)198.5 °CPhysProp
water solubility1.11E+005 mg/L (at 20 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP-1.78HANSCH,C ET AL. (1995)
logS-0.13ADME Research, USCD
pKa1.8MERCK for CO; NH2-7.9; thiol-10.5
Predicted Properties
PropertyValueSource
Water Solubility4.65 mg/mLALOGPS
logP-1.7ALOGPS
logP-2.1ChemAxon
logS-1.5ALOGPS
pKa (Strongest Acidic)2.56ChemAxon
pKa (Strongest Basic)9.09ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area63.32 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity37.22 m3·mol-1ChemAxon
Polarizability14.76 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9278
Blood Brain Barrier+0.5821
Caco-2 permeable-0.7778
P-glycoprotein substrateNon-substrate0.7679
P-glycoprotein inhibitor INon-inhibitor0.9818
P-glycoprotein inhibitor IINon-inhibitor0.9959
Renal organic cation transporterNon-inhibitor0.9744
CYP450 2C9 substrateNon-substrate0.776
CYP450 2D6 substrateNon-substrate0.8636
CYP450 3A4 substrateNon-substrate0.7038
CYP450 1A2 substrateInhibitor0.8476
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9528
CYP450 2C19 inhibitorNon-inhibitor0.9187
CYP450 3A4 inhibitorNon-inhibitor0.9107
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9693
Ames testAMES toxic0.6358
CarcinogenicityNon-carcinogens0.6495
BiodegradationNot ready biodegradable0.8739
Rat acute toxicity2.0294 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9987
hERG inhibition (predictor II)Non-inhibitor0.962
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (7.76 KB)
Spectra
SpectrumSpectrum TypeSplash Key
GC-MS Spectrum - GC-EI-TOFGC-MSsplash10-0fr5-1930000000-6ee8522d7087601d49e6
GC-MS Spectrum - GC-EI-TOFGC-MSsplash10-00di-9520000000-1ac6006c4f882c72292b
GC-MS Spectrum - GC-EI-TOFGC-MSsplash10-00di-9640000000-736237ccaaa4ef171daa
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 valine and derivatives. These are compounds containing valine or a derivative thereof resulting from reaction of valine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Valine and derivatives
Alternative Parents
D-alpha-amino acids / Thia fatty acids / Methyl-branched fatty acids / Amino acids / Monocarboxylic acids and derivatives / Carboxylic acids / Alkylthiols / Organopnictogen compounds / Organic oxides / Monoalkylamines
show 2 more
Substituents
Valine or derivatives / Alpha-amino acid / D-alpha-amino acid / Branched fatty acid / Methyl-branched fatty acid / Thia fatty acid / Fatty acyl / Fatty acid / Amino acid / Alkylthiol
show 15 more
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
penicillamine (CHEBI:7959)

Targets

Kind
Small molecule
Organism
Human
Pharmacological action
Yes
Actions
Chelator
References
  1. Brewer GJ: Novel therapeutic approaches to the treatment of Wilson's disease. Expert Opin Pharmacother. 2006 Feb;7(3):317-24. [PubMed:16448326]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. Gui C, Hagenbuch B: Role of transmembrane domain 10 for the function of organic anion transporting polypeptide 1B1. Protein Sci. 2009 Nov;18(11):2298-306. doi: 10.1002/pro.240. [PubMed:19760661]

Drug created on June 13, 2005 07:24 / Updated on November 19, 2017 20:34