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-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.
Ahmadi
M
M
Welsh School of Pharmacy, UWCC, Cardiff, UK.
Khalaf
L F
LF
Smith
H J
HJ
Nicholls
P J
PJ
D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D003622:Dapsone / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005493:Folic Acid Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism
D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D006635:Histamine H2 Antagonists; D002927:Cimetidine; D003622:Dapsone