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Description of key information

Male rats are the most sensitive species tested, while Humans are the least sensitive ones. Dapsone is rapidly excreted with a half-life of 7.7 - 14 hours in all three species. Methemoglobinaemia is the most prominent adverse effects observed. The major metabolite is dapsone-hydroxylamine and Dapsone-hydroxylamine-glucuronide. No bio-accumulation is expected based on the excretion half-life and logPow.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
75
Absorption rate - dermal (%):
15

Additional information

Dapsone is absorbed rapidly and nearly completely from the gastrointestinal tract. Peak concentrations of dapsone in plasma are reached within 2 to 8 hours after administration. The mean half-life of elimination is about 20 to 30 hours. Twenty-four hours after oral ingestion of 100 mg, plasma concentrations range from 0.4 to 1.2 µg/ml, and a dose of 100 mg per day produces steady-state plasma concentrations of free dapsone of 2 to 6 µmol/L. About 70% of the drug is bound to plasma protein.

Dapsone is distributed throughout total body water and is present in all tissues. However, it tends to be retained in skin and muscle and especially in the liver and kidney: traces of the drug are present in these organs up to 3 weeks after therapy cessation.

After absorption from the gastrointestinal tract, dapsone is transported through the portal circulation to the liver, where it is metabolized by two distinct routes, N-acetylation and N-hydroxylation. Dapsone toxicity, in particular methemoglobin formation, is putatively initiated by N-oxidation, resulting in the formation of a hydroxylamine metabolite by cytochrome P450. A recent study showed that the P450 accounting for the majority of dapsone hydroxylamine formation in vivo is the CYP2E1. To a lesser extent, CYP2C also metabolizes dapsone. A single dose of disulfiram, a slowly reversing inhibitor of CYP2E1 in vivo, inhibited dapsone hydroxylamine formation clearance by 73%, and inhibited methemoglobin formation by 78% in a group of healthy volunteers. Dapsone-induced methemoglobin formation in healthy volunteers was also diminished by 61% following the administration of cimetidine, a relatively non-selective P450 inhibitor. The authors speculated that the treatment-limiting toxicities of dapsone might be diminished by co-administration of a suitable inhibitor of hydroxylamine formation, as evidenced in their study.

Previous studies found the forms CYP3A4, CYP 2C6/2C11 and 3A1 and CYP 1A2 to play the greatest role in the N-oxidation of dapsone.

The fate of the toxic metabolite of dapsone, dapsone hydroxylamine, has been studied in the human red cell. The parent amine was produced from dapsone hydroxylamine during methemoglobin formation in the red cells, and there was a linear relationship between hydroxylamine-dependent methemoglobin formation and conversion of hydroxylamine to dapsone. The authors suggested that a cycle exists between the hepatic oxidation of dapsone to its hydroxylamine form and reduction to amine within the red cell, a process, which might lead to re-oxidation by the hepatic cytochrome P450. They speculated that this process might contribute to the persistence of the drug in vivo.

N-oxidation represents a major route of Dapsone metabolism in man. 4,4'-DDS is rapidly metabolized in Humans as well as in rats and Guinea pigs. The same N-hydroxy DDS (DDS-NOH) metabolite is found in all three species, excretion is within 3-5 days with an excretion half-life of approx 24 hours. DDS-NOH is the most effective of the metabolites in oxydizing hemoglobin to methemoglobin in the erythrocyte in presence of O2and glucose. DDS-NOH can be recycled in erythrocyte by NADPH in presence of GSH (reduced glutathione). Human data (supporting study) show that human dermal absorption is less than 1/20 of the absorption rate in the rat or rabbit.