Inhibition of Dapsone-induced Methaemoglobinaemia by Cimetidine in the Presence of Trimethoprim in the Rat

Abstract

Abstract Administration of dapsone in combination with trimethoprim and cimetidine to male rats resulted in a marked decrease (P < 0·05) in measured methaemoglobin levels (46·2±24% Met Hb h) compared with administration of dapsone alone (124·5 ± 24·4% Met Hb h). The elimination half-life of dapsone (814 ± 351 min) was more than doubled in the presence of trimethoprim and cimetidine compared with control (355 ± 160 min, P < 0·05). However, there were no significant differences in AUC and clearance when dapsone was administered in combination with trimethoprim and cimetidine compared with dapsone alone. Co-administration of trimethoprim with dapsone in the absence of cimetidine did not affect either methaemoglobin formation, AUCs, half-lives, or clearance values of dapsone compared with control. There was a threefold increase in the AUC of trimethoprim (6296 ± 2249 μg min mL−1) in the presence of dapsone compared with trimethoprim alone (2122 ± 552 μg min mL−1). There was also a corresponding decrease in the clearance of trimethoprim in the presence of dapsone compared with control (19·1±6·9 vs 60·8 ± 21·0 mL min−1). However, there was no change in the elimination half-life of trimethoprim between the two experimental groups (273 ± 120 vs 292 ± 54 min). The AUC of trimethoprim increased more than threefold in the presence of cimetidine (7100 ± 1501 μg min mL−1) compared with trimethoprim alone (2122 ± 552 μg min mL−1). There was also a corresponding reduction in the clearance of trimethoprim in the presence of cimetidine (61·2 ± 21·2 vs 17·8 ± 9·3 mL min−1) compared with control. However, there was no significant change in the elimination half-life of trimethoprim after the administration of cimetidine (273 ± 136 vs 215 ± 109 min). Administration of either trimethoprim or cimetidine alone did not cause methaemoglobin levels to exceed control values. The administration of trimethoprim with dapsone and cimetidine resulted in a significant increase in AUC (2122 ± 552 vs 5744 ± 3289 μg min mL−1), a fall in clearance (17·8 ± 9·3 vs 60·8 ± 21 mL min−1), but no change in half-life (252 ± 134 vs 273 ± 136 h) of trimethoprim. The co-administration of cimetidine significantly reduced dapsone-mediated methaemoglobin formation in the presence of trimethoprim, whilst the AUC of trimethoprim was significantly increased in the presence of both cimetidine and dapsone.