Penicillamine

Last updated

Penicillamine
Penicillamine structure.svg
Clinical data
Trade names Cuprimine, Cuprenyl, Depen, others
Other names
  • D-penicillamine
  • (–)-penicillamine
, 3-mercapto-L-valine, 3-mercaptovaline
AHFS/Drugs.com Monograph
MedlinePlus a618021
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth (capsules)
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Variable
Metabolism Liver
Elimination half-life 1 hour
Excretion Kidney
Identifiers
  • (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.136 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C5H11NO2S
Molar mass 149.21 g·mol−1
3D model (JSmol)
  • CC(C)([C@H](C(=O)O)N)S
  • InChI=1S/C5H11NO2S/c1-5(2,9)3(6)4(7)8/h3,9H,6H2,1-2H3,(H,7,8)/t3-/m0/s1 Yes check.svgY
  • Key:VVNCNSJFMMFHPL-VKHMYHEASA-N Yes check.svgY
   (verify)

Penicillamine, sold under the brand name of Cuprimine among others, is a medication primarily used for the treatment of Wilson's disease. [1] It is also used for people with kidney stones who have high urine cystine levels, rheumatoid arthritis, and various heavy metal poisonings. [1] [2] It is taken by mouth. [2]

Contents

Penicillamine was approved for medical use in the United States in 1970. [1] It is on the World Health Organization's List of Essential Medicines. [3]

Medical uses

It is used as a chelating agent:

In cystinuria, a hereditary disorder in which high urine cystine levels lead to the formation of cystine stones, penicillamine binds with cysteine to yield a mixed disulfide which is more soluble than cystine. [8]

Penicillamine has been used to treat scleroderma. [9]

Penicillamine can be used as a disease-modifying antirheumatic drug (DMARD) to treat severe active rheumatoid arthritis in patients who have failed to respond to an adequate trial of conventional therapy, [10] although it is rarely used today due to availability of TNF inhibitors and other agents, such as tocilizumab and tofacitinib. Penicillamine works by reducing numbers of T-lymphocytes, inhibiting macrophage function, decreasing IL-1, decreasing rheumatoid factor, and preventing collagen from cross-linking.

Adverse effects

Common side effects include rash, loss of appetite, nausea, diarrhea, and low white blood cell levels. [1] Other serious side effects include liver problems, obliterative bronchiolitis, and myasthenia gravis. [1] It is not recommended in people with lupus erythematosus. [2] Use during pregnancy may result in harm to the baby. [2] Penicillamine works by binding heavy metals; the resulting penicillamine–metal complexes are then removed from the body in the urine. [1]

Bone marrow suppression, dysgeusia, anorexia, vomiting, and diarrhea are the most common side effects, occurring in ~20–30% of the patients treated with penicillamine. [11] [12]

Other possible adverse effects include:

Chemistry

D-Penicillamine.svg
D-(–)-(S)-Penicillamine
(antiarthritic)
L-Penicillamine.svg
L-(+)-(R)-Penicillamine
(toxic)

Penicillamine is a trifunctional organic compound, consisting of a thiol, an amine, and a carboxylic acid. It is an amino acid structurally similar to cysteine, but with geminal dimethyl substituents α to the thiol. Like most amino acids, it is a colorless solid that exists in the zwitterionic form at physiological pH. The acid-base properties of penicillamine and cysteine are very similar. The pKa for the carboxylic acid is 1.8 for both, and the pKa for the thiol and ammonium groups are 10.8 (cys) and 10.5 and 8.3 (cys) and 7.9. [19]

Penicillamine is chiral molecule. The natural form has the opposite configuration from the one seen for natural cysteine. [19] The two enantiomers have distinct physiological effects. (S)-penicillamine (D-penicillamine, having (–) optical rotation) is used as aa drug (a chiral drug). [20] (R)-penicillamine (L-penicillamine, having (+) optical rotation) is toxic because it inhibits the action of pyridoxine (also known as vitamin B6). [21] D-penicillamine is a metabolite of penicillin but has no antibiotic properties itself. A variety of metal complexes derived from penicillamine are known. [22] For example, copper form large clusters. [23]

History

John Walshe first described the use of penicillamine in Wilson's disease in 1956. [24] He had discovered the compound in the urine of patients (including himself) who had taken penicillin, and experimentally confirmed that it increased urinary copper excretion by chelation. He had initial difficulty convincing several world experts of the time (Denny-Brown and Cumings) of its efficacy, as they held that Wilson's disease was not primarily a problem of copper homeostasis but of amino acid metabolism, and that dimercaprol should be used as a chelator. Later studies confirmed both the copper-centered theory and the efficacy of D-penicillamine. Walshe also pioneered other chelators in Wilson's such as triethylene tetramine and tetrathiomolybdate. [25]

Penicillamine was first synthesized by John Cornforth under supervision of Robert Robinson. [26]

Penicillamine has been used in rheumatoid arthritis since the first successful case in 1964. [27]

References

  1. 1 2 3 4 5 6 "Penicillamine". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  2. 1 2 3 4 World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 64, 592. hdl:10665/44053. ISBN   9789241547659.
  3. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  4. ↑ Peisach J, Blumberg WE (March 1969). "A mechanism for the action of penicillamine in the treatment of Wilson's disease". Molecular Pharmacology. 5 (2): 200–209. doi:10.1016/S0026-895X(25)14659-2. PMID   4306792.
  5. ↑ Aaseth J, Skaug MA, Cao Y, Andersen O (2015). "Chelation in metal intoxication--Principles and paradigms". Journal of Trace Elements in Medicine and Biology. 31: 260–266. Bibcode:2015JTEMB..31..260A. doi:10.1016/j.jtemb.2014.10.001. PMID   25457281.
  6. ↑ Peterson RG, Rumack BH (October 1977). "D-penicillamine therapy of acute arsenic poisoning". The Journal of Pediatrics. 91 (4): 661–666. doi:10.1016/S0022-3476(77)80528-3. PMID   908992.
  7. ↑ Hall AH (March 2002). "Chronic arsenic poisoning". Toxicology Letters. 128 (1–3): 69–72. doi:10.1016/S0378-4274(01)00534-3. PMID   11869818.
  8. 1 2 Rosenberg LE, Hayslett JP (August 1967). "Nephrotoxic effects of penicillamine in cystinuria". JAMA. 201 (9): 698–699. doi:10.1001/jama.1967.03130090062021. PMID   6071831.
  9. ↑ Steen VD, Medsger TA, Rodnan GP (November 1982). "D-Penicillamine therapy in progressive systemic sclerosis (scleroderma): a retrospective analysis". Annals of Internal Medicine. 97 (5): 652–659. doi:10.7326/0003-4819-97-5-652. PMID   7137731.
  10. ↑ "Cuprimine (penicillamine) Capsules for Oral Use. U.S. Full Prescribing Information" (PDF). Archived (PDF) from the original on 8 September 2015. Retrieved 29 April 2016.
  11. 1 2 3 Camp AV (February 1977). "Penicillamine in the treatment of rheumatoid arthritis". Proceedings of the Royal Society of Medicine. 70 (2): 67–69. doi:10.1177/003591577707000201. PMC   1542978 . PMID   859814.
  12. ↑ Grasedyck K (1988). "D-penicillamine--side effects, pathogenesis and decreasing the risks". Zeitschrift für Rheumatologie. 47 (Suppl 1): 17–19. PMID   3063003.
  13. 1 2 Fishel B, Tishler M, Caspi D, Yaron M (July 1989). "Fatal aplastic anaemia and liver toxicity caused by D-penicillamine treatment of rheumatoid arthritis". Annals of the Rheumatic Diseases. 48 (7): 609–610. doi:10.1136/ard.48.7.609. PMC   1003826 . PMID   2774703.
  14. ↑ Mitchell RS, Kumar V, Abbas AK, Fausto N (2007). "Table 14-2". Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. ISBN   978-1-4160-2973-1.
  15. ↑ Chalmers A, Thompson D, Stein HE, Reid G, Patterson AC (November 1982). "Systemic lupus erythematosus during penicillamine therapy for rheumatoid arthritis". Annals of Internal Medicine. 97 (5): 659–663. doi:10.7326/0003-4819-97-5-659. PMID   6958210.
  16. ↑ Bolognia J, Rapini RP, Jorizzo JL, Jorizzo JL, Schaffer JV (2007). Dermatology (2nd ed.). Philadelphia: Elsevier. ISBN   978-1-4160-2999-1.
  17. ↑ Underwood JC (2009). General and Systemic Pathology. Elsevier Limited. ISBN   978-0-443-06889-8.
  18. ↑ Taylor PJ, Cumming DC, Corenblum B (January 1981). "Successful treatment of D-penicillamine-induced breast gigantism with danazol". British Medical Journal. 282 (6261): 362–363. doi:10.1136/bmj.282.6261.362-a. PMC   1504185 . PMID   6780026.
  19. 1 2 Yoshinari N, Konno T (2018). "Chiral Phenomena in Multinuclear and Metallosupramolecular Coordination Systems Derived from Metalloligands with Thiol-Containing Amino Acids". Bulletin of the Chemical Society of Japan. 91 (5): 790–812. doi:10.1246/bcsj.20180032.
  20. ↑ Ariens EJ (1989). Chiral Separations by HPLC. Chichester: Ellis Horwwod, Chichester. pp. 31–68.
  21. ↑ Aronson JK (2010). Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs. Amsterdam: Elsevier Science. p. 613. ISBN   9780080932941. Archived from the original on 10 September 2017.
  22. ↑ Yoshinari N, Konno T (2018). "Chiral Phenomena in Multinuclear and Metallosupramolecular Coordination Systems Derived from Metalloligands with Thiol-Containing Amino Acids". Bulletin of the Chemical Society of Japan. 91 (5): 790–812. doi:10.1246/bcsj.20180032.
  23. ↑ Birker PJ, Freeman HC (October 1977). "Structure, properties, and function of a copper(I)-copper(II) complex of D-penicillamine: pentathallium(I) μ8-chloro-dodeca(D-penicillaminato)-octacuprate(I)hexacuprate(II) n-hydrate". Journal of the American Chemical Society. 99 (21): 6890–6899. doi:10.1021/ja00463a019. PMID   903530.
  24. ↑ Walshe JM (January 1956). "Wilson's disease; new oral therapy". Lancet. 270 (6906): 25–26. doi:10.1016/S0140-6736(56)91859-1. PMID   13279157.
  25. ↑ Walshe JM (August 2003). "The story of penicillamine: a difficult birth". Movement Disorders. 18 (8): 853–859. doi:10.1002/mds.10458. PMID   12889074. S2CID   11406561.
  26. ↑ Oakes EH (2007). Encyclopedia of World Scientists. Infobase Publishing. p. 156. ISBN   9781438118826.
  27. ↑ Jaffe IA (September 1964). "Rheumatoid Arthritis with Arteritis; Report of a Case Treated with Penicillamine". Annals of Internal Medicine. 61: 556–563. doi:10.7326/0003-4819-61-3-556. PMID   14218939.
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