title: The effect of preincubation with cimetidine on the N-hydroxylation of dapsone by human liver microsomes.
abstract: We have examined the ability of cimetidine to inhibit the oxidative metabolism and hence haemotoxicity of dapsone in vitro, using a two compartment system in which two Teflon chambers are separated by a semi-permeable membrane. Compartment A contained a drug metabolizing system (microsomes prepared from human or rat liver +/- NADPH), whilst compartment B contained human red cells. Preincubation (30 min) of human liver microsomes with cimetidine (0-1000 microM) and NADPH prior to the addition of dapsone (100 microM) and NADPH (1 mM) resulted in a concentration-dependent decrease in the concentrations of dapsone hydroxylamine (from 179 +/- 47 to 40 +/- 6 ng) in compartment B. This reduction of hydroxylamine metabolite was reflected in the concentration-dependent reduction in methaemoglobin measured (from 7.1 +/- 0.7 to 3.5 +/- 1.5%) in parallel experiments. Preincubation of microsomes with cimetidine in the absence of NADPH had no effect. The effect of cimetidine pretreatment on dapsone-dependent methaemoglobin was confirmed using microsomes prepared from a further three sources of human liver, as well as from rat liver.
authors.affiliation: Department of Pharmacology and Therapeutics, Liverpool.
authors.forename: M D
authors.initials: MD
authors.lastname: Tingle
authors.forename: M D
authors.initials: MD
authors.lastname: Coleman
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002927:Cimetidine / Q000494:pharmacology*; D003622:Dapsone / Q000031:analogs & derivatives / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D008297:Male; D008706:Methemoglobin / Q000096:biosynthesis; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D009249:NADP / Q000494:pharmacology; D051381:Rats
chemical_list: D009249:NADP; D002927:Cimetidine; D003622:Dapsone; D008706:Methemoglobin; C018209:4-amino-4'-hydroxylaminodiphenylsulfone