Penicillamine metal complexes

I. Pharmacology. Penicillamine is a derivative of penicillin that has no antimicrobial activity but effectively chelates some heavy metals such as lead, mercury, and copper. It has been used as adjunctive therapy after initial treatment with calcium EDTA (see p 440) or BAL (dimercaprol p 413), although its use has largely been replaced by the oral chelator sucdmer (DMSA, p 501) because of its poor safety profile. Penicillamine is well absorbed orally, and the penicillamine-metal complex is eliminated in the urine. No parenteral form is available. 

Penicillamine is known to form complexes of varying stability with several metal ions. In neutral solution, penicillamine complexes with mercury, lead, nickel, and copper are relatively more stable than those of zinc, iron, and manganese. The three functional groups of penicillamine may be engaged in the formation of metal complex, and the resultant compounds may be polymeric in structure. 

Pectic acids metal complexes, 984 Penicillamine disulfide... 

Doornbos DA, Faber JS. Studies on metal complexes of drugs. D-penicillamine and N-acetyl-D-peniciUamine. Pharm Weekbl 1964 99 289-309. 

Doornbos DA. Stabihty constants of metal complexes of L-cysteine, D-penicillamine, N-acetyl-D-peniciUamine and some biguanides. Determination of stoichiometric stabihty constants by an accurate method for pH measurement. Pharm Weekbl 1968 103(45) 1213-27. 

D-penicillamine is so named because it was first isolated as an amine, from the degradation products of penicillin by Abraham et al [87]. Later studies showed the characteristic chemical behavior of D-penicillamine which involve three types of reactions, formation of disulphide links, formation of thiazolidine rings, and formation of metal complexes and chelates [67]. It was first used in 1956 in the treatment of Wilson s disease [88]. D-penicillamine has since been used in the treatment of many diseases, such as cystinuria [89], rheumatoid arthritis [90-92], systemic sclerosis [93], primary bdiary cirrhosis [94], heavy metal poisoning due to lead [95], cadmium [%], and mercury [97], and hyperviscosity syndrome [99]. In rheumatoid arthritis, D-peni-cdlamine has been widely accepted as an effective second line treatment. Despite of its effectiveness, it causes many adverse effects, such as skin rashes [99,100], taste abnormalities [100,101], hepatic dysfunction [102-104], gastrointestinal toxiciiy [99,105], proteinuria [100,106], hematuria [107, 108], thrombocytopenia [92, 109], aplastic anemia [110], lupus-like syndrome [111, 112], Goodpasture s-tike pulmonary renal syndrome [113-115], vasculitis [116,117], myasthenia gravis [118-122], polymyositis [123, 124], and dermatomyositis [125]. 

Doombos DA and Faber J, Metal complexes of dmgs. d-penicillamine and N-acetyl-o-penicillamine, Pharm. Weekbl., 99, 289-309 (1964). 

Zucconi TD, Janauer GE, Donahe S and Lewkowicz C, Acid dissociation and metal complex formation constants of penicillamine, cysteine, and antiarfiiritic gold complexes at simulated biological conditions,/. Pharm. Sci, 68(4), 426-432 (1979). 

An ionophoretic method was described by Tewari [41] for the study of equilibria in a mixed ligand complex system in solution. This method is based on the movement of a spot of metal ion in an electric field with the complexants added in the background electrolyte at pH 8.5. The concentration of the primary ligand (nitrilo-triacetate) was kept constant, while that of the secondary ligand (penicillamine) was varied. The stability constants of the metal nitrilotriacetate-penicillamine complexes have been found to be 6.26 0.09 and 6.68 0.13 (log K values) for the Al(III) and Th(IV) complexes, respectively, at 35 °C and an ionic strength of 0.1 M. 

The (n)-enantiomer of penicillamine is used clinically in man either as the hydrochloride or as the free amino acid [1], although the (L)-enantiomer also forms chelation complexes. Penicillamine is an effective chelator of copper, mercury, zinc, and lead, and other heavy metals to form stable, soluble complexes that are readily excreted in the urine [2,3]. 

Poisoning - Penicillamine also forms soluble complexes with iron, mercury, lead, and arsenic, which are readily excreted by the kidneys. The drug may be used to treat poisoning by these metals. 

Chemical structures of several chelators. Ferroxamine (ferrioxamine) without the chelated iron is deferoxamine. It is represented here to show the functional groups the iron is actually held in a caged system. The structures of the in vivo metal-chelator complexes for dimercaprol, succimer, penicillamine, and unithiol (see text) are not known and may involve the formation of mixed disulfides with amino acids. 

Although such reactions have been known for a long time, it appears a somewhat neglected area of study. Most attention has been on cysteine and its oxidation to the disulfide which is catalyzed by metal ions, in particular CuI[ (see Section 20.2.2.2.2) and FeI,[.81 The likely intermediates in these reactions are metal-cysteine complexes which undergo internal electron transfer. As noted earlier (Section 20.2.2.2.2), penicillamine differs from cysteine in its reactivity and gives rise to mixed valence species. More recently Mn11 has also been found to catalyze the oxidations of Cys and Pen. 

C104) crystallizes in 96% yield in a second-order asymmetric manner. The solution actually contains the equilibrium mixture A(jR) A(jR) = 7 3.1036 Both Co2, and OH- effect rapid mutarota-tion about the metal in this complex but not about the chiral carbon. With (S)-penicillamine a similar equilibrium obtains (A A[Co (S)pen (en)2]2+ = 7 3) but preferential crystallization does not occur.1037 X-Ray structures confirm equatorial and axial dangling carboxylate functions in A-[Co (R)cys (en)2](C104) and A-[Co (7 )cy s (en)2 ] (C104) H2 O respectively.1037 (N,S) bonding seems to be preferred in (N,S,0) systems (cysteine, penicillamine) but (N,0)[Co (R)cys (en)2]2+ has been prepared by reduction of the tridentate sulfenamide complex (285 equation 159).1038 This (N.O) chelate lacks the extended charge transfer absorptions in the near UV characteristic of thiolate coordination. 

Penicillamine is a potent chelator of metals. The stability of complexes of metals with penicillamine varies in the following order (from highest to lowest) mercury, lead, nickel, copper, zinc, cadmium, cobalt, iron, manganese (136-138). Most human data refer to copper, lead, and mercury. 

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