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Clinical Pharmacokinetics of D-Penicillamine

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Summary

Penicillamine exists as 2 stereoisomers, but only the D-isomer is used therapeutically. Its chemical reactivity derives from its functional groups, of which the thiol group seems the most important.

It is difficult to determine penicillamine in biological fluids because of its instability, the presence of endogenous compounds with a thiol function, and the various chemical forms in which it occurs, namely reduced free penicillamine, penicillamine bound to proteins, and internal (P-S-S-P) and mixed (P-S-S-C) disulphides. The earliest assay methods (colourimetry, isotopic methods, gas-phase chromatography) were neither sensitive nor specific. High performance liquid chromatography with electrochemical detection has led to a more specific assay for D-penkillamine, with detection based on either derivatisation reactions or on electro-oxidisation of the thiol function. With dual-electrode detectors (Au/Hg) disulphides can be assayed directly.

D-penicillamine is absorbed rapidly but incompletely (40 to 70%) in the intestine, with wide interindividual variations. Food, antacids and, in particular, iron reduce absorption of the drug. Its bioavailability is also dramatically decreased in patients with malabsorption states. The peak plasma concentration occurs at 1 to 3 hours after ingestion, regardless of dose, and is of the order of 1 to 2 mg/L after an oral dose of 250mg; some investigators have reported a double peak in plasma, which is probably not due to an enterohepatic cycle. The concentration in plasma then decreases rapidly, generally following a biphasic curve. When long term treatment is discontinued, there is a slow elimination phase lasting 4 to 6 days, which suggests that there is a ‘deep compartment’ or ‘slow pool of the drug reversibly bound to tissues’, particularly the skin. This may explain the persistence of its therapeutic effect and the occurrence of undesirable side effects after treatment has been stopped.

During long term treatment plasma concentrations are highly variable between individuals. They do not seem to be correlated with the activity or the toxicity of D-penicillamine in patients with rheumatoid arthritis. More than 80% of plasma D-penicillamine is bound to proteins, particularly albumin. The rest is mainly in the free reduced form or as disulphides. Only a small portion of the dose is metabolised in the liver to S-methyl-D-penicillamine. The route of elimination is mainly renal; disulphides represent the main compounds found in the urine. Faecal excretion corresponds mainly to the non-absorbed fraction of the drug.

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  1. Département de Pharmacologie Clinique, Clinique Rhumatologique and Laboratoire de Chimie Analytique, Université de Nancy I, Nancy, France

    Patrick Netter, Bernard Bannwarth, Patrice Péré & Alain Nicolas

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Netter, P., Bannwarth, B., Péré, P. et al. Clinical Pharmacokinetics of D-Penicillamine. Clin-Pharmacokinet 13, 317–333 (1987). https://doi.org/10.2165/00003088-198713050-00003

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