Inhibition of Dapsone-Induced Methaemoglobinaemia by Cimetidine in the Rat During Chronic Dapsone Administration

Abstract

— 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 < 0.05) Met Hb AUC (757 ± 135 vs 584 ± 115% Met Hb h), dapsone AUC (140 ± 17.5 vs 113 ± 130 μg h mL⁻¹) and monoacetyl dapsone AUC (48.2 ± 18.3 vs 10.8 ± 4.6 μg 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 < 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 μg h mL⁻¹) and monoacetyl dapsone AUC values (33.6 ± 5.8 vs 10.8 ± 4.0 μg h mL⁻¹) compared with a single daily dose of dapsone (group I). Administration of cimetidine before the twice daily dose of dapsone (group IV) resulted in no significant change in Met Hb or monoacetyl dapsone levels, despite a marked increase in the AUC after dapsone compared with control (303 ± 53.2 vs 140 ± 17.5 μg h mL⁻¹ P < 0.05; group II). The administration of a single dose of monoacetyl dapsone alone resulted in rapid production of methaemoglobinaemia (17.1 ± 7.2%) at 1 h; however, prior administration of cimetidine did not significantly affect methaemoglobin levels over 24 h (287.6 ± 77.9 vs 316.4 ± 120.2% Met Hb h). These studies indicate that although cimetidine may reduce Met Hb formation during chronic dapsone administration, dose reduction of dapsone is required to avoid haemotoxicity because of the increased accumulation of both parent drug and its monoacetyl metabolite.