title: 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 micrograms min mL-1) was almost three-fold higher than control (345.0 +/- 68.1 micrograms min mL-1, P less than 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 less than 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 less than 0.01). The AUC0-3h for DDS-NOH (28.3 +/- 21.2 micrograms min mL-1) was significantly reduced by cimetidine (8.1 +/- 3.40 micrograms min mL-1, P less than 0.01). In contrast, there was a marked increase in the AUC0-3h for MADDS (32.7 +/- 25.8 micrograms min mL-1) in the presence of cimetidine (166.0 +/- 26.5 micrograms min mL-1 P less than 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.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, UK.
authors.forename: M D
authors.initials: MD
authors.lastname: Coleman
authors.forename: P E
authors.initials: PE
authors.lastname: Hoaksey
authors.forename: A M
authors.initials: AM
authors.lastname: Breckenridge
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002927:Cimetidine / Q000494:pharmacology; D003622:Dapsone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006207:Half-Life; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet
chemical_list: D002927:Cimetidine; D003622:Dapsone; C018965:monoacetyldapsone