Inhibition of Dapsone-induced Methaemoglobinaemia in the Rat Isolated Perfused Liver

Abstract

We have investigated the disposition of dapsone (DDS, 1 mg) in the rat isolated perfused liver in the absence and the presence of cimetidine (3 mg). After the addition of DDS alone to the liver there was a monoexponential decline of parent drug concentrations and rapid formation of DDS-NOH (within 10 min) which coincided with methaemoglobin formation (11.7 ± 3.0%, mean ± s.d.) which reached a maximum (22.6 ± 9.2%) at 1 h. The appearance of monoacetyl DDS (MADDS) was not apparent until 30–45 min. Addition of cimetidine resulted in major changes in the pharmacokinetics of DDS and its metabolites. The AUC of DDS in the presence of cimetidine (1018.8 ± 267.8 μg min mL−1) was almost three-fold higher than control (345.0 ± 68.1 μg min mL−1, P < 0.01). The half-life of DDS was also prolonged by cimetidine compared with control (117.0 ± 48.2 min vs 51.2 ± 22.9, P < 0.05). The clearance of DDS (3.0 ± 0.55 mL min−1) was greatly reduced in the presence of cimetidine (1.03 ± 0.26 mL min−1 P < 0.01). The AUC0.3 h for DDS-NOH (28.3 ± 21.2 μg min mL−1) was significantly reduced by cimetidine (8.1 ± 3.40 μg min mL−1, P < 0.01). In contrast, there was a marked increase in the AUC0.3 h for MADDS (32.7 ± 25.8 μg min mL−1) in the presence of cimetidine (166.0 ± 26.5 μg min mL−1 P < 0.01). The methaemoglobinaemia associated with DDS was reduced to below 5% by cimetidine. Hence, a shift in hepatic metabolism from bioactivation (N-hydroxylation) to detoxication (N-acetylation) caused by cimetidine, was associated with a fall in methaemoglobinaemia. These data suggest that the combination of DDS with a cytochrome P450 inhibitor might reduce the risk to benefit ratio of DDS.