CUPRIMINE Capsule Ref.[10789] Active ingredients: Penicillamine

Penicillamine is a chelating agent recommended for the removal of excess copper in patients with Wilson’s disease. From in vitro studies which indicate that one atom of copper combines with two molecules of penicillamine, it would appear that 1 g of penicillamine should be followed by the excretion of about 200 mg of copper; however, the actual amount excreted is about 1% of this.

Penicillamine also reduces excess cystine excretion in cystinuria. This is done, at least in part, by disulfide interchange between penicillamine and cystine, resulting in formation of penicillamine-cysteine disulfide, a substance that is much more soluble than cystine and is excreted readily.

Penicillamine interferes with the formation of cross-links between tropocollagen molecules and cleaves them when newly formed.

The mechanism of action of penicillamine in rheumatoid arthritis is unknown although it appears to suppress disease activity. Unlike cytotoxic immunosuppressants, penicillamine markedly lowers IgM rheumatoid factor but produces no significant depression in absolute levels of serum immunoglobulins. Also unlike cytotoxic immunosuppressants which act on both, penicillamine in vitro depresses T-cell activity but not B-cell activity.

In vitro, penicillamine dissociates macroglobulins (rheumatoid factor) although the relationship of the activity to its effect in rheumatoid arthritis is not known.

In rheumatoid arthritis, the onset of therapeutic response to CUPRIMINE may not be seen for 2 or 3 months. In those patients who respond, however, the first evidence of suppression of symptoms such as pain, tenderness, and swelling is generally apparent within 3 months. The optimum duration of therapy has not been determined. If remissions occur, they may last from months to years, but usually require continued treatment (see DOSAGE AND ADMINISTRATION).

In all patients receiving penicillamine, it is important that CUPRIMINE be given on an empty stomach, at least 1 hour before meals or 2 hours after meals, and at least 1 hour apart from any other drug, food, milk, antacid, zinc, or iron-containing preparation. This permits maximum absorption and reduces the likelihood of inactivation by metal binding in the gastrointestinal tract.

Pharmacokinetics

Penicillamine is absorbed rapidly but incompletely (40-70%) from the gastrointestinal tract, with wide inter-individual variations. Food, antacids, and iron reduce absorption of the drug. The peak plasma concentration of penicillamine occurs 1 to 3 hours after ingestion; it is approximately 1 to 2 mg/L after an oral dose of 250 mg. The drug appears in the plasma as free penicillamine, penicillamine disulfide, and penicillamine-cysteine disulfide. When prolonged treatment is stopped, there is a slow elimination phase lasting 4 to 6 days.

More than 80% of plasma penicillamine is bound to proteins, especially albumin and ceruloplasmin. The drug also binds to erythrocytes and macrophages. A small fraction of the dose is metabolized in the liver to S-methyl-D-penicillamine. Excretion is mainly renal, mainly as disulfides.