Metabolism and Excretion

After absorption in the gastrointestinal tract, dapsone is transported to the liver, where it undergoes different metabolic transformations. The two major metabolic pathways involve N-acetylation and N-hydroxylation. Dapsone and its derivatives are acetylated by N-acetyltranferase to the nontoxic metabolites MADDS and diacetyl-dapsone. As with several other drugs, such as isoniazid and hydralazine, patients show genetic polymorphism in their ability to acetylate dapsone; some patients rapidly acetylate dapsone to MADDS ("rapid" acetylators), whereas in others this process occurs slowly ("slow" acetylators). Deacetylation occurs simultaneously, and a stable equilibrium between MADDS and dapsone is reached within a few hours of oral administration. However, it seems that the rate of acetylation does not relate to the half-life in the body and does not affect the efficacy of the drug. The other major metabolic pathway is hydroxylation, and it is responsible for hematologic side effects, such as methemoglobinemia, hemolysis, and Heinz-body formations. N-Hydroxy-lation is effected by a variety of cytochrome P-450 enzymes (CYP3A, CYP2E, and CYP2C) forming hydroxylamine, a potentially toxic metabolite, using hepatic microsomes. The levels of expression of these cytochrome P-450 enzymes may be crucial for individual vulnerability to dapsone side effects. Finally, dapsone, MADDS, and hydroxylamine are conjugated in the liver with glucuronic acid in preparation for excretion. Approximately 85%-90% of dapsone is excreted in the urine, primarily as glucuronide. Only 10% is excreted in the bile. Approximately 50% of a single dose of dapsone is excreted within the first 24 h. Probenecid decreases the renal clearance of dapsone, whereas rifampicin increases urinary excretion. Since dapsone is subject to enterohepatic circulation, administration of activated charcoal decreases its elimination half-life by 50% (Katz 1999, Lang 1979, Zhu and Stiller 2001, Zuidema et al. 1989).

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