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Clinical Pharmacokinetics of Dapsone

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Summary

Dapsone (DDS) has for about 4 decades been the most important antileprosy drug. Concentrations of dapsone and its monoacetyl metabolite, MADDS, can be determined in biological media by high-performance liquid chromatography. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. However, the extent of absorption has not been adequately determined. The elimination half-life of dapsone is about 30 hours. The drug shows linear pharmacokinetics within the therapeutic range and the time-course after oral administration fits a 2-compartment model.

The concentration-time profile of dapsone after parenteral administration is reviewed. Of clinical importance is the development of a new long acting injection, which permits monthly supervised administration as recommended by the World Health Organization. Following dapsone injection in gluteal subcutaneous adipose tissue, a sufficiently sustained absorption for this purpose has been reported.

Dapsone is about 70 to 90% protein bound and its monoacetylated metabolite (MADDS) is almost completely protein bound. The volume of distribution of dapsone is estimated to be 1.5 L/kg. It is distributed in most tissues, but M. leprae living in the Schwann cells of the nerves might be unaffected. Dapsone crosses the placenta and is excreted in breast milk and saliva.

Dapsone is extensively metabolised. Dapsone, some MADDS and their hydroxylated metabolites are found in urine, partly conjugated as N-glucuronides and N-sulphates. The acetylation ratio (MADDS: dapsone) shows a genetically determined bimodal distribution and allows the definition of ‘slow’ and ‘rapid’ acetylators. As enterohepatic circulation occurs, the elimination half-life of dapsone is markedly decreased after oral administration of activated charcoal. This permits successful treatment in cases of intoxication.

The daily dose of dapsone in leprosy is 50 to 100mg, but varies from 50 to 400mg in the treatment of other dermatological disorders. In malaria prophylaxis, a weekly dose of 100mg is used in combination with pyrimethamine. Side effects are mostly not serious below a daily dose of 100mg and are mainly haematological effects. The dapsone therapeutic serum concentration range can be defined as 0.5 to 5 mg/L.

Alcoholic liver disease decreases the protein binding of dapsone; coeliac disease and dermatitis herpetiformis may delay its oral absorption and severe leprosy has been reported to affect the extent of absorption.

Rifampicin increases the rate of elimination of dapsone; pyrimethamine increases the volume of distribution and probenecid decreases the renal clearance of dapsone.

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  1. Department of Biopharmaceutics, University of Amsterdam, Plantage Muidergracht 14, 1018 TV, Amsterdam, The Netherlands

    J. Zuidema, E. S. M. Hilbers-Modderman & F. W. H. M. Merkus

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Zuidema, J., Hilbers-Modderman, E.S.M. & Merkus, F.W.H.M. Clinical Pharmacokinetics of Dapsone. Clin-Pharmacokinet 11, 299–315 (1986). https://doi.org/10.2165/00003088-198611040-00003

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