A Dapsone-induced Blood Dyscrasia in the Mouse: Evidence for the Role of an Active Metabolite

Abstract

In the female mouse, dapsone (50-500 mg kg-1, p.o.) caused a dose-related methaemoglobinaemia which peaked at 0.5-1 h with recovery to baseline values occurring by 4 h. Cimetidine (100 mg kg-1, p.o.), a known inhibitor of several hepatic P450 isozymes administered 1 h before dapsone, prevented the methaemoglobinaemia. In-vitro, dapsone required activation by mouse hepatic microsomes to cause methaemoglobin formation in mouse erythrocytes and cytotoxicity to human mononuclear leucocytes. In both instances, the toxic effects were markedly reduced by cimetidine. Daily dosing of mice with dapsone (50 mg kg-1, p.o.) for 3 weeks induced a blood dyscrasia, characterized by a fall of platelet and white blood cell counts, which was inhibited by cimetidine (100 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 genesis not only of the methaemoglobinaemia but also the blood dyscrasia arising from repeated administration of the drug in this species.

Clinical outcomes and kinetics of propanil following acute self-poisoning: a prospective case series

“…[ 45 ] Co-administration of cimetidine and dapsone inhibits formation of the hydroxylamine metabolite of dapsone and methaemoglobin. [ 16 , 46 - 49 ] A similar effect is possible for propanil poisoning if DCA interacts with the same CYP450 enzymes, but no data are available and it is possible detoxifying enzymes might also be inhibited. There have been no clinical studies assessing whether such treatment has a role in clinical management.…”

“…[ 11 - 15 ] These reactions are similar to those of dapsone which are well characterised: the severity of methaemoglobinaemia relates to the amount of dapsone's hydroxylamine metabolite, which varies with dose and cytochrome P450 activity. [ 16 , 17 ] We therefore expect that there will be a proportional relationship between the concentration of propanil and its metabolites and clinical toxicity, although this has not yet been confirmed in humans.…”