Penicillamine

Brand Names: Cuprimine, Depen

Clinical Names: Penicillamine

Summary

generic name: Penicillamine

trade names: Cuprimine, Depen

type of drug: Chelating agent.

mechanism: Penicillamine increases the urinary excretion of copper.

used to treat: Wilson's disease (hepatolenticular degeneration), cystinuria, chronic lead poisoning, and in patients with recalcitrant, severe rheumatoid arthritis.

Wilson's disease is an inherited disease of copper accumulation caused by a failure of biliary excretion of excess copper. Accumulated copper causes liver disease in these patients, and in perhaps two thirds of patients, it causes brain damage leading to clinical neurologic or psychiatric dysfunction. Maintenance treatment involves reversing the positive copper balance.

overview of interactions:
• nutrient affected by drug: Vitamin B6 (Pyridoxine)

• nutrient affecting drug performance: Copper

• nutrient affecting drug toxicity: Iron

• nutrient affected by drug: Sodium

• nutrient affected by drug: Zinc

• diet affecting drug performance: Food



Interactions

nutrient affected by drug: Vitamin B6 (Pyridoxine)

• nutritional support: Due to increased excretion and reduced activity of vitamin B6, penicillamine increases the risk of pyridoxine deficiency and the requirement for pyridoxine supplementation. Because of their dietary restrictions, individuals with Wilson's disease and cystinuria using penicillamine would benefit from 25 mg per day of pyridoxine during therapy. Rheumatoid arthritis patients whose nutrition is impaired should also be given a daily supplement of pyridoxine. In general, individuals taking penicillamine for any reason should supplement with the relatively small dose of 5-20 mg of vitamin B6 daily.
(Jaffe IA. Ann N Y Acad Sci 1969 Sep 30;166(1):57-60; Bhagavan HN, Brin M. Curr Concepts Nutr 1983;12:1-12.)

nutrient affecting drug performance: Copper

• research: Among the primary therapeutic uses of penicillamine is the treatment of Wilson's disease where toxic deposits of copper accumulate.

• nutritional concerns: Given the therapeutic objective of reducing toxic levels of copper in the body by increasing urinary excretion of the mineral, individuals with Wilson's disease should never consume copper supplements of any kind, even in the small doses found in most multivitamin/mineral formulas. In individuals taking penicillamine to reduce copper levels the consumption of any supplemental copper would obviously have an adverse effect on the drug's performance.

nutrient affecting drug toxicity: Iron

• mechanism: The role of penicillamine is to bind metals and iron is among the metals thus affected. When iron and penicillamine are taken together chelation of penicillamine by iron in the gut reduces its absorption and activity.

• nutritional support: During the course of penicillamine therapy iron deficiency can often develop, especially in children and in menstruating women. In Wilson's disease, this may be a result of adding the effects of the low copper diet, which is probably also low in iron, and the penicillamine to the effects of blood loss or growth. In cystinuria, a low methionine diet may contribute to iron deficiency, since it is inherently low in protein.

• nutritional concerns: Orally administered iron has been shown to reduce the effects of penicillamine. If necessary, iron may be given in short courses, but a period of at least two hours, or preferably eight hours, should elapse between administration of penicillamine and iron supplements or other iron-containing products.

Great caution needs to exercised when changing the level of iron intake in individuals taking penicillamine. Problems have been reported where the prescribing physician has been unaware that a patient has been using concomitant supplemental iron and responded to the lack of therapeutic response to penicillamine by increasing the drug dose. In one report of four patients toxicity only became apparent after iron was stopped and there was a sudden increase in penicillamine absorption with resulting penicillamine-induced kidney damage.
(Threlkeld DS, ed. Aug 1996; Harkness JA, Blake DR. Lancet 1982 Dec 18;2(8312):1368-1369.)

nutrient affected by drug: Sodium

• nutritional concerns: Some researchers have reported an association between penicillamine therapy and sodium depletion. The frequency and clinical significance of this association remains unclear.

nutrient affected by drug: Zinc

• mechanism: Zinc blocks the absorption of copper and increases copper excretion in the stool. Because of the high level of endogenously secreted copper in alimentary secretions, the reabsorption of which is partially blocked by zinc therapy, zinc acts to remove accumulated copper from the body as well as prevent its reaccumulation.

• nutritional concerns: Just as it chelates a variety of other minerals, penicillamine can bind zinc and interfere with the absorption of both penicillamine and zinc.

• nutritional support: Some nutritionally oriented physicians have begun treating individuals with Wilson's disease with zinc instead of penicillamine. This type of combined therapy using large-dose zinc sulfate and low-dose penicillamine has become recognized as an safe, effective and inexpensive treatment for children with hepatolenticular degeneration. However, individuals taking penicillamine should avoid zinc-containing supplements unless specifically recommended by their prescribing physician or another nutritionally trained healthcare professional.
(Anderson LA, et al. Ann Pharmacother 1998 Jan;32(1):78-87; Brewer GJ, et al. J Lab Clin Med 1998 Oct;132(4):264-278; Li T, et al. Chung Hua I Hsueh I Chuan Hsueh Tsa Chih 1999 Feb 10;16(1):19-21.)

diet affecting drug performance: Food

• research: Normal dietary intake can significantly interfere with penicillamine absorption. In one study penicillamine levels were reduced to 52% of those from the fasting dose after food.
(Osman MA, et al. Clin Pharmacol Ther 1983 Apr;33(4):465-470; Schuna A, et al. J Rheumatol 1983 Feb;10(1):95-97.)

• nutritional concerns: It is generally recommended that penicillamine be taken on an empty stomach or, more exactly, one hour before or two hours after any food to avoid this interaction.

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References

Anderson LA, Hakojarvi SL, Boudreaux SK. Zinc acetate treatment in Wilson's disease. Ann Pharmacother 1998 Jan;32(1):78-87. (Review)
Abstract: OBJECTIVE: To briefly review the pathophysiology and diagnosis of Wilson's disease, and to evaluate the pharmacology, pharmacokinetics, clinical utility, adverse effects, dosing regimens, and pharmacoeconomics of zinc acetate therapy in Wilson's disease. DATA SOURCES: A MEDLINE search (December 1966-December 1996) of the English-language literature using the terms zinc and Wilson's disease was conducted to identify pertinent clinical trials, review articles, and case reports. Additional articles were selected from bibliographies of the reviewed literature. STUDY SELECTION AND DATA EXTRACTION: Due to the rarity of the disease, all articles were considered for possible inclusion in this review. Single case reports are referenced, but were not selected for evaluation. DATA SYNTHESIS: Wilson's disease, an inherited disorder of copper metabolism, is fatal if untreated. The chelating drugs penicillamine and trientine have been the mainstay of therapy; however, adverse reactions of chelators often interfere with successful treatment. Recently, zinc acetate was approved in the US for maintenance therapy in patients initially treated with a chelating agent. Although studies evaluating large populations are lacking zinc therapy has demonstrated exceptional safety and efficacy over a period of 40 years. Zinc acetate can be used during pregnancy and for the treatment of presymptomatic patients, although data do not support its use as monotherapy in patients with acute neurologic or hepatic disease. CONCLUSIONS: Zinc acetate is an effective maintenance therapy for patients with Wilson's disease. Negligible toxicity, compared with that of previously approved treatments, is a major advantage.

Bhagavan HN, Brin M. Drug--vitamin B6 interaction. Curr Concepts Nutr 1983;12:1-12. (Review)
Abstract: In conclusion, there are several drug types that can interfere with vitamin B6 metabolism. In most cases, the interaction involves a complex formation between the drug (or a derivative) and the reactive coenzyme PLP, resulting in a Schiff base. Such an interaction leads to an inactivation of PLP (and also of the drug). Other types of interaction involve (a) stimulation of vitamin B6-dependent pathways and (b) competition with PLP for the binding site on the enzyme. Examples of the above are the steroid hormones (oral contraceptives). In most instances, overt symptoms of vitamin B6 deficiency due to chronic ingestion of these drugs are observed, and neurological problems seem to be rather frequent. Because of the reactive nature of the coenzyme PLP and the ease with which it can interact with drugs, sub-clinical (marginal) vitamin B6 deficiency should be suspected in the absence of overt clinical signs. Once the vitamin B6 problem has been identified, the condition can usually be treated by judicious use of large doses of vitamin B6 without compromising the clinical efficacy of the drug.

Brewer GJ, Dick RD, Johnson VD, Brunberg JA, Kluin KJ, Fink JT. Treatment of Wilson's disease with zinc: XV long-term follow-up studies. J Lab Clin Med 1998 Oct;132(4):264-278.
Abstract: Wilson's disease is an inherited disease of copper accumulation caused by a failure of biliary excretion of excess copper. Accumulated copper causes liver disease in these patients, and in perhaps two thirds of patients, it causes brain damage leading to clinical neurologic or psychiatric dysfunction. Maintenance treatment involves reversing the positive copper balance. The earliest approaches have used chelators, such as penicillamine or trientine, which increase the urinary excretion of copper. A more recent approach has used zinc, which blocks the absorption of copper and increases copper excretion in the stool. Because of the high level of endogenously secreted copper in alimentary secretions, the reabsorption of which is partially blocked by zinc therapy, zinc acts to remove accumulated copper from the body as well as prevent its reaccumulation. In the present article we present data on the long-term follow-up (up to 10 years) of maintenance zinc treatment of 141 patients with Wilson's disease. The data presented document that zinc is effective as a sole therapy in the long-term maintenance treatment of Wilson's disease and that it has a low toxicity. The results demonstrate the efficacy of zinc therapy in treating the presymptomatic patient from the beginning of therapy. We also present limited data on the use of zinc in the treatment of pregnant patients and children who have Wilson's disease; these data also indicate efficacy and low toxicity. The median follow-up period for the group as a whole is 4.8 years; for the presymptomatic patients it is 6.5 years; for the children it is 3.6 years.

Harkness JA, Blake DR. Penicillamine nephropathy and iron. Lancet 1982 Dec 18;2(8312):1368-1369.
Abstract: 7 of 16 patients with rheumatoid arthritis in whom penicillamine glomerulonephritis had developed had been taking oral iron, usually without the knowledge of their hospital clinician, while the dose of penicillamine was being gradually increased to an effective level. In 4 patients glomerulonephritis had appeared after the patients had stopped iron, with proteinuria developing with 2-5 months of discontinuation. Chelation of penicillamine by iron in the gut reduces its absorption, and in these 4 patients toxicity only became apparent after iron was stopped and there was a sudden increase in penicillamine absorption.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998, 201-203.

Jaffe IA. Antivitamin B6 effect of D-penicillamine. Ann N Y Acad Sci 1969 Sep 30;166(1):57-60.

Jaffe IA. The antivitamin B 6 effect of penicillamine: clinical and immunological implications. Adv Biochem Psychopharmacol 1972;4:217-226. (Review)

Li T, Lin R, Du S, Qu Z. [Long-term follow-up of combined therapy with large-dose zinc sulfate and low-dose penicillamine in children with hepatolenticular degeneration]. Chung Hua I Hsueh I Chuan Hsueh Tsa Chih 1999 Feb 10;16(1):19-21. [Article in Chinese]
Abstract: OBJECTIVE: To summarize the long-term effect of combined treatment with large-dose zinc sulfate and low-dose penicillamine in children with hepatolenticular degeneration (HLD). METHODS: The patients who had symptoms were treated with large-dose zinc sulfate (100-150mg, <6yr; 150-200mg, 6-8yr; 200-300mg, 9-10yr; 300mg,>10yr; 3 times a day) in addition to low-dose penicillamine(8-10mg/kg/d) at the beginning of treatment. Zinc sulfate alone was given to the presymptomatic patients and it was used as maintenance therapy when clinical improvement was obtained. 31 children were followed up for 4-11 years. RESULTS: In 3 presymptomatic patients, no clinical abnormalities were found. Among 28 patients with symptoms, 23 patients (82%) had their symptoms and signs subsided or much improved, 2 patients(7%) remained unchanged, and 3(11%) died. Blood concentrations of copper were persistently lower than normal. Urine copper excretion of 24 hours was significantly lower than that before the combined therapy in all patients, and it became normal in 5 cases(16%) after 6 months of treatment, and in 26 cases(84%) after 1-2 years of treatment. Higher blood concentrations of zinc were found in 20 cases(65%), and higher urine zinc excretion was noted in 25 cases(81%) once or more times during the therapy. CONCLUSION: Combined therapy of large-dose zinc sulfate and low-dose penicillamine is an effective, safe and cheap treatment for children with HLD.

Lyle WH. Penicillamine and iron. Lancet 1976 Aug 21;2(7982):420. (Letter)

Osman MA, Patel RB, Schuna A, Sundstrom WR, Welling PG. Reduction in oral penicillamine absorption by food, antacid, and ferrous sulfate. Clin Pharmacol Ther 1983 Apr;33(4):465-470.
Abstract: Plasma levels of penicillamine, urinary recovery of penicillamine and its oxidized metabolites, and urinary excretion of copper were examined after single 500-mg oral doses of penicillamine to six healthy men. Penicillamine was given after an overnight fast, a standard breakfast, and after antacid and ferrous sulfate. Following the fasting dose, the mean peak plasma level of 3.05 micrograms/ml developed at 3.8 hr and the drug was cleared from plasma with a t1/2 of 2.1 hr. Penicillamine levels were reduced to 52%, 35%, and 66% of those from the fasting dose after food, ferrous sulfate, and antacid. The rates of penicillamine appearance and disappearance from plasma were essentially treatment independent. There were good correlations between urinary recovery of total penicillamine (r = 0.875), between urinary copper excretion (r = 0.758) and the penicillamine plasma concentration AUCs. The availability of oral penicillamine is very susceptible to interactions with other substances. Further studies may be necessary to assess the full clinical significance of these interactions.

Schilsky ML. Wilson disease: genetic basis of copper toxicity and natural history. Semin Liver Dis 1996 Feb;16(1):83-95. (Review)
Abstract: The discovery that the gene for Wilson disease encodes a copper-transporting ATPase has greatly improved our understanding of the pathophysiology of this disorder and of copper metabolism in humans. The abundance of disease-specific mutations and their location at multiple sites across the genome have limited molecular genetic diagnosis to kindred of known patients, and confirm the necessity for de novo screening by well-proven clinical and biochemical means. It is uncertain whether the variety of specific mutations will account for the wide range of presenting clinical signs and symptoms of Wilson disease, and environmental and extragenic factors are likely to be important contributing factors. Chelation therapy with penicillamine and trientine remain effective treatment for most symptomatic hepatic and neurologic Wilson disease. Zinc salts may be used for some asymptomatic patients, and OLT for fulminant hepatitis and patients for whom pharmacotherapy is ineffective. The chelating agent tetrathiomolybdate is under investigation for the treatment of neurologic Wilson disease. Gene therapy is the new horizon for treatment of Wilson disease. However, the ability to treat this disorder effectively by this means awaits further characterization of the gene product and more efficient methods for gene delivery to all hepatocytes in the liver.

Schuna A, Osman MA, Patel RB, Welling PG, Sundstrom WR. Influence of food on the bioavailability of penicillamine. J Rheumatol 1983 Feb;10(1):95-97.
Abstract: The relative bioavailability of D-penicillamine was determined after single 500 mg oral doses of commercial tablets to healthy male volunteers under fasting and nonfasting conditions. In fasted individuals the mean maximum penicillamine level in plasma of 3.05 mcg/ml occurred at 3.8 h, and the area under the 0-12 h plasma curve was 14.7 mcg/h/ml. In nonfasted individuals the mean maximum penicillamine level of 1.52 mcg/ml occurred at 2.3 h, and the area under the 0-12 h plasma curve was reduced to 7.16 mcg/h/ml. Thus under these conditions food reduced systemic penicillamine availability by 1/2, but did not reduce the apparent absorption rate.

Threlkeld DS, ed. Miscellaneous Products, Penicillamine. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Aug 1996.