Penicillamine excretion

Treatment for Wilson disease consists of a diet low in copper along with Ufelong administration of penicillamine, which chelates copper, is excreted in the urine, and thus depletes the body of the excess of this mineral. 

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]. 

Cystinuria. Penicillamine reduces excess cystine excretion in cystinuria. Penicillamine with conventional therapy decreases crystalluria and stone formation, and may decrease the size of or dissolving existing stones. This is achieved by disulfide interchange between penicillamine and cystine, resulting in a substance more soluble than cystine and readily excreted. 

Treatment. Since the 1950s, the treatment of Wilson s disease has relied on chelating agents [25]. Early attempts to use BAL or EDTA for this purpose were unsuccessful, but penicillamine, triethylene tetramine dihydrochloride (trientine), and tetrathiomolybdate, all in combination with a low-copper diet, have proved to be effective, and result in the urinary excretion of large amounts of copper. The use of penicillamine is complicated by the fact that it may induce a transient worsening of neurologic function due to rapid mobilization of copper, and also has other side-effects, such as the development of nephrosis. Tetrathiomolybdate is an effective alternative with fewer side-effects [26]. In cases in which the dose was rapidly escalated, however, bone marrow suppression or liver function abnormalities have been described. 

In mammals, phenobarbital and phenytoin increase serum ceruloplasmin concentrations (Aaseth and Norseth 1986). Chronic copper poisoning in sheep is exacerbated when diets contain heliotrope plants (Heliotropium sp., Echium spp., Senecio sp.). Aggravated effects of the heliotrope plants include reduced survival and a twofold to threefold increase in liver and kidney copper concentrations when compared to control animals fed copper without heliotropes (Howell et al. 1991). Rats given acutely toxic doses of 2,3,7,8-tetrachlorodibenzo-para-dioxin had elevated concentrations of copper in liver and kidney because of impaired biliary excretion of copper (Elsenhans et al. 1991). Morphine increases copper concentrations in the central nervous system of rats, and dithiocarbam-ates inhibit biliary excretion (Aaseth and Norseth 1986). In human patients, urinary excretion of copper is increased after treatment with D-penicillamine, calcium disodium EDTA, or calcium trisodium diethylenetriamine penta acetic acid (Flora 1991). 

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. 

Pharmacokinetics It is well absorbed from the Gl tract after oral administration (40% to 70%) peak plasma levels occur in 1 to 3 hours. Most (80%) of the plasma penicillamine is protein bound, primarily to albumin. Penicillamine is rapidly excreted in the urine 50% is excreted in the feces. Metabolites may be detected in the urine for up to 3 months after stopping the drug. Half-life ranges are 1.7 to 3.2 hours. 

Combination with penicillamine is contraindicated as penicillamine is a metal chelator. However penicillamine can be used to treat gold toxicity. N-acetylcysteine can also increase the excretion of gold. 

Penicillamine (Cuprimine) can be used to treat acute, severe rheumatoid arthritis, producing reductions in joint pain, edema, and stiffness. The response to penicillamine is usually delayed (4-12 weeks), and remissions can last several months after withdrawal of treatment. Radiographic evidence of this drug s efficacy is limited thus, penicillamine is seldom used to treat rheumatoid arthritis. The mechanism of action of penicillamine is unknown, but some evidence suggests that it may involve the inhibition of angiogenesis, synovial fibroblast proliferation, or transcriptional activation. Because penicillamine can chelate copper and promote its excretion, it is used to treat Wilson s disease (hepatolenticular degeneration) and has also been used in mercury and lead intoxication. 

Penicillamine is readily absorbed from the GI tract and is rapidly excreted in the urine, largely as the intact molecule. Gradually increasing its dose minimizes side effects, which necessitate discontinuance of penicillamine therapy in perhaps one-third of patients. The most common side effects are maculopapular pruritic dermatitis, GI upset, loss of taste sensation, mild to occasionally severe thrombocytopenia and leukopenia. 

Mechanism of Action Asulfhydryl compound with similar properties to those of penicillamine and glutathione that undergoes thiol-disulfide exchange with cysteine to form tiopronin-cysteine, a mixed disulfide. This disulfide is water soluble, unlike cysteine, and does not crystallize in the kidneys. May break disulfide bonds present in bronchial secretions and break the mucus complexes. Therapeutic Effect Decreases cysteine excretion. 

The exact mechanisms of action of penicillamine in rheumatoid arthritis is not known. After oral administration it is partly metabolised and partly excreted unchanged. 

For patients who are unable to tolerate penicillamine, trientine, another chelating agent, may be used in a daily dose of 1-1.5 g. Trientine appears to have few adverse effects other than mild anemia due to iron deficiency in a few patients. Zinc acetate administered orally increases the fecal excretion of copper and is sometimes used for maintenance therapy. The dose is 50 mg three times a day. Zinc sulfate (200 mg/d orally) has also been used to decrease copper absorption. Zinc blocks copper absorption from the gastrointestinal tract by induction of intestinal cell metallothionein. Its main advantage is its low toxicity compared with that of other anticopper agents, although it may cause gastric irritation when introduced. 

Penicillamine is used chiefly for treatment of poisoning with copper or to prevent copper accumulation, as in Wilson s disease (hepatolenticular degeneration). It is also used occasionally in the treatment of severe rheumatoid arthritis (see Chapter 36). Its ability to increase urinary excretion of lead and mercury had occasioned its use in outpatient treatment for intoxication with these metals, but succimer, with its stronger metal-mobilizing capacity and lower adverse-effect profile, has generally replaced penicillamine for these purposes. 

These thiolate exchange reactions are thought to lead to incorporation of gold(I) to thiolate functions in proteins and enzymes, and thence to interfere with the inflammatory process. Thiols such as 2,3-dimercaptopropanol (BAL), iV-acetylcysteine and penicillamine have also been used in the treatment of gold toxicity. Protein-bound gold is mobilized by complexation to the added thiol and can then be excreted.250,273... 

Penicillamine had a small effect on urinary glucaric acid excretion in patients with rheumatoid arthritis (923). This effect was thought to be the result of an indirect effect on hepatic metabolism and not to be related to disease activity. 

These agents bind the copper so that it is solublized and excreted in the urine. They are effective because of their high affinity for copper(II) over other metals in the body. Although both isomers of penicillamine bind copper equally well it has been found that the L-form is toxic. Interestingly D-penicillamine is also used to treat rheumatoid arthritis where it acts to reduce collagen crosslinking the enzymes responsible for this process are largely copper centred. 

Wilson s disease is a copper storage disorder that is apparently due to an inherited lesion in the copper excretion mechanism. One in 200-400 persons is a carrier of the disease. Diagnosis may be made by measuring serum ceruloplasmin levels. Whereas normal serum ceruloplasmin is 200-400 mg/L, in Wilson s disease patients it is well below 200 mg/L. Liver copper in these patients (determined by biopsy) is more than 250 /xg/g, whereas normal individuals show a value of only 20-45 /xg/g. Liver function deterioration is the most prominent symptom of Wilson s disease. Treatment includes chelation therapy with penicillamine. 

Disposition in the Body. Readily but incompletely absorbed after oral administration. About 50% of an oral dose is excreted in the urine in 48 hours with about 10% as unchanged drug, up to 25% as cysteine-penicillamine disulphide, about 15% as penicillamine disulphide, and less than 10% as 5 -methyl-D-penicillamine about 35% of an oral dose is eliminated in the faeces in 3 days. After intravenous administration, about 80% of the dose is excreted in the urine in 24 hours traces of penicillamine remain in the plasma after 48 hours due to protein binding. 

Copper toxicity has been observed, althongh it is not a function of dietary overload. Abnormally low levels of ceruloplasmin associated with the genetic disorder, Wilson s disease, lead to excessive deposition of copper in the central nervous system, ocular tissue, liver, and other organs. Severe psychotic symptoms are observed. Urinary excretion of the copper can be achieved with specific chelating agents such as British anti-lewisite (BAL, 2,3-dimercaptopropanol) or penicillamine, orally administered. Symptoms of the disease are reversed as the copper levels return to normal. Reduction of dietary copper nptake by competition with relatively high levels of oral zinc is also effective. ... 

D-Penicillamine Reduction and chelation of copper. Urinary excretion of copper by mobilizing copper from organs 1 - 2 g orally in divided doses... 

Trientine (triethylenetetramine) was used in 1982 to treat Wilson disease as an alternative to D-peiticillamtne. It is also a chelator of copper and increases urinary excretion of copper. There is less experience with the use of trientine compared to D-penicillamine. Its toxicity is relatively unexplored. The initial effect of this treatment is large cupriuresis but its rate diminishes more rapidly than with D-penicillamine. However, it should be pointed out that this treatment is effective especially in situations for which D-penicillamine must be... 

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