Inhibition of dapsone-induced methaemoglobinaemia by cimetidine in the rat during chronic dapsone administration.
Dapsone undergoes N-acetylation to monoacetyl dapsone as well as N-hydroxylation to a hydroxylamine which is responsible for the haemotoxicity (i.e. methaemoglobinaemia; Met Hb) of the drug. Since dapsone is always given chronically, we have investigated the ability of cimetidine to inhibit Met Hb formation caused by repeated dapsone administration. The drug was given (i.p.) to four groups (n = 6 per group) of male Wistar rats, 300-360 g. Group I received 10 mg kg-1 at 1, 24, 48 and 72 h. Group II received 10 mg kg-1 at 1, 8, 24, 32, 48, 56, 72 and 80 h. Groups III and IV received the drug as for groups I and II, respectively, as well as cimetidine (50 mg kg-1) 1 h before each dose of dapsone. Twice daily dapsone administration (Group II) resulted in a significantly greater (P less than 0.05) Met Hb AUC (757 +/- 135 vs 584 +/- 115% Met Hb h), dapsone AUC (140 +/- 17.5 vs 113 +/- 13.0 micrograms h mL-1) and monoacetyl dapsone AUC (48.2 +/- 18.3 vs 10.8 +/- 4.6 micrograms h mL-1) compared with a single daily dapsone dose (group I). The administration of cimetidine before the once daily dose of dapsone (group III) resulted in a significant (P less than 0.05) fall in Met Hb (302 +/- 179 vs 584 +/- 115% Met Hb h) and an increase in both the dapsone (151 +/- 22.2 vs 113 +/- 13.0 micrograms h mL-1) and monoacetyl dapsone AUC values (33.6 +/- 5.8 vs 10.8 +/- 4.0 micrograms h mL-1) compared with a single daily dose of dapsone (group I).(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
M D
MD
Coleman
M D
MD
Tingle
B K
BK
Park
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002927:Cimetidine / Q000494:pharmacology*; D003622:Dapsone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D006900:Hydroxylation; D008297:Male; D008708:Methemoglobinemia / Q000097:blood / Q000139:chemically induced*; D051381:Rats; D011919:Rats, Inbred Strains
D002927:Cimetidine; D003622:Dapsone; C018965:monoacetyldapsone