A DAPSONE-INDUCED BLOOD DYSCRASIA IN THE MOUSE - EVIDENCE FOR THE ROLE OF AN ACTIVE METABOLITE

In the female mouse, dapsone (50-500 mg kg(-1), p.o.) caused a dose-re lated methaemoglobinaemia which peaked at 0.5-1 h with recovery to bas eline values occurring by 4 h. Cimetidine (100 mg kg(-1), p.o.), a kno wn inhibitor of several hepatic P450 isozymes administered Ih before d apsone, prevented the methaemoglobinaemia. In-vitro, dapsone required activation by mouse hepatic microsomes to cause methaemoglobin formati on in mouse erythrocytes and cytotoxicity to human mononuclear leucocy tes. In both instances, the toxic effects were markedly reduced by cim etidine. Daily dosing of mice with dapsone cell (50 mg kg(-1), p.o.) f or 3 weeks induced a blood dyscrasia, characterized by a fall of plate let and white blood cell counts, which was inhibited by cimetidine (10 0 mg kg(-1), p.o. daily). It is concluded that an active metabolite of dapsone arising from a P450-dependent pathway is involved in the gene sis not only of the methaemoglobinaemia but also the blood dyscrasia a rising from repeated administration of the drug in this species.