InWilson's disease, a rare genetic disorder ofcopper metabolism, penicillamine treatment relies on its binding to accumulated copper and elimination through urine.[4]Succimer (dimercaptosuccinic acid) is increasingly used in place of penicillamine.[5]
Incystinuria, a hereditary disorder in which high urine cystine levels lead to the formation ofcystine stones, penicillamine binds with cysteine to yield a mixeddisulfide which is moresoluble than cystine.[8]
Penicillamine is a trifunctional organic compound, consisting of athiol, anamine, and acarboxylic acid. It is anamino acid structurally similar tocysteine, but withgeminal dimethylsubstituents α to the thiol. Like most amino acids, it is a colorless solid that exists in thezwitterionic form atphysiological 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 ischiral molecule. The natural form has the opposite configuration from the one seen for natural cysteine.[19] The twoenantiomers have distinctphysiological effects.(S)-penicillamine (D-penicillamine, having (–)optical rotation) is used as a drug (achiral drug).[20](R)-penicillamine (L-penicillamine, having (+) optical rotation) is toxic because it inhibits the action ofpyridoxine (also known asvitamin B6).[21]D-penicillamine is ametabolite ofpenicillin but has noantibiotic properties itself. A variety of metal complexes derived from penicillamine are known.[19] For example, copper form large clusters.[22]
John Walshe first described the use of penicillamine in Wilson's disease in 1956.[23] He had discovered the compound in the urine of patients (including himself) who had takenpenicillin, and experimentally confirmed that it increased urinary copper excretion bychelation. 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 thatdimercaprol should be used as a chelator. Later studies confirmed both the copper-centered theory and the efficacy ofD-penicillamine. Walshe also pioneered other chelators in Wilson's such astriethylene tetramine andtetrathiomolybdate.[24]
^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.
^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.PMID4306792.
^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.PMID7137731.
^Grasedyck K (1988). "D-penicillamine--side effects, pathogenesis and decreasing the risks".Zeitschrift für Rheumatologie.47 (Suppl 1):17–19.PMID3063003.
^Mitchell RS, Kumar V, Abbas AK, Fausto N (2007). "Table 14-2".Robbins Basic Pathology (8th ed.). Philadelphia: Saunders.ISBN978-1-4160-2973-1.
^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.PMID6958210.
^abcYoshinari 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.
^Ariens EJ (1989).Chiral Separations by HPLC. Chichester: Ellis Horwwod, Chichester. pp. 31–68.
^Birker PJ, Freeman HC (October 1977). "Structure, properties, and function of a copper(I)-copper(II) complex ofD-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.PMID903530.
^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.PMID14218939.
