title: Effects of H(2)-receptor antagonists on dapsone-induced methaemoglobinaemia in rats.
abstract: Dapsone (DDS) (4,4'diaminodiphenylsulfone), the drug of choice for the treatment of leprosy, frequently induces haemolytic anaemia and methaemoglobinaemia. N-hydroxylation, one of the major pathways of biotransformation, has been constantly related to the methaemoglobinaemia observed with the use of the drug. In order to determine the reversible inhibition of this toxicologic bioactivation pathway without changing the detoxification pathways of the drug or cytosolic acetylation, cimetidine (CIM), ranitidine and famotidine were administered in combination with DDS to male Wistar rats weighing 200-220 g. The animals were divided into nine groups of eight: group 1 received a single dose of 40 mg kg (-1) DDS in dimethylsulfoxide (DMSO) and groups 2-4 received the same treatment as group 1 but after the administration of a single dose of 100, 150 and 200 mg kg (-1) CIM, respectively, injected 2 h prior DDS administration. Groups 5-9 received the same treatment as group 2 but after the treatment of ranitidine (50 and 100 mg kg (-1) intraperitoneally (i.p.) in 200 microl DMSO) and famotidine (10, 50 and 100 mg kg (-1) i.p. in 200 microl DMSO), respectively. The animals were then anaesthetized with ether and blood was collected from the aorta for the determination of plasma DDS and monoacetyldapsone concentrations by HPLC and later for the determination of methaemoglobinaemia by spectrophotometry. CIM showed a higher affinity for cytochrome P-450 than famotidine and ranitidine. The results obtained showed the potentiality of the pharmacological effects of DDS with a low risk of adverse reactions, especially methaemoglobinaemia, which is dose dependent.
authors.affiliation: Department of Clinical, Toxicological and Food Sciences Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av.Café s/n, 14040-903 Ribeirão Preto São Paulo, Brazil.
authors.forename: Wilson Roberto
authors.initials: WR
authors.lastname: Malfará
authors.forename: Carolina Paula
authors.initials: CP
authors.lastname: Pereira
authors.forename: Antonio Cardozo Dos
authors.initials: AC
authors.lastname: Santos
authors.forename: Regina Helena Costa
authors.initials: RH
authors.lastname: Queiroz
mesh_terms: D000818:Animals; D001711:Biotransformation; D003622:Dapsone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000097:blood / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015738:Famotidine / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007917:Leprostatic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced* / Q000517:prevention & control*; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D006635:Histamine H2 Antagonists; D007917:Leprostatic Agents; D015738:Famotidine; D011899:Ranitidine; D003622:Dapsone; C018965:monoacetyldapsone