Depen (Penicillamine) - Description and Clinical Pharmacology

DESCRIPTION - Penicillamine is 3-mercapto-D-valine, a disease modifying antirheumatic drug. It is a white or practically white, crystalline powder, freely soluble in water, slightly soluble in alcohol, and insoluble in ether, acetone, benzene, and carbon tetrachloride. Although its configuration is D, it is levorotatory as usually measured:

The empirical formula is C₅H₁₁NO₂S, giving it a molecular weight of 149.21. The structural formula is:

It reacts readily with formaldehyde or acetone to form a thiazolidine-carboxylic acid.

Depen® (penicillamine tablets, USP) Titratable Tablets for oral administration contain 250 mg of penicillamine.

Other ingredients (inactive): edetate disodium, hypromellose, lactose, magnesium stearate, magnesium trisilicate, polyethylene glycol, povidone, simethicone emulsion, starch, and stearic acid.

CLINICAL PHARMACOLOGY - 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 one gram of penicillamine should be followed by the excretion of about 200 milligrams of copper; however, the actual amount excreted is about one percent 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 DEPEN may not be seen for two or three months. In those patients who respond, however, the first evidence of suppression of symptoms such as pain, tenderness, and swelling usually is generally apparent within three 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 DEPEN be given on an empty stomach, at least one hour before meals or two hours after meals, and at least one hour apart from any other drug, food or milk. This permits maximum absorption and reduces the likelihood of inactivation by metal binding in the gastrointestinal tract.

Methodology for determining the bioavailability of penicillamine is not available; however, penicillamine is known to be a very soluble substance.