title: Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo.
abstract: Dapsone toxicity is putatively initiated by formation of a hydroxylamine metabolite by cytochromes P450. In human liver microsomes, the kinetics of P450-catalyzed N-oxidation of dapsone were biphasic, with the Michaelis-Menten constants of 0.14 +/- 0.05 and 0.004 +/- 0.003 mmol/L and the respective maximum velocities of 1.3 +/- 0.1 and 0.13 +/- 0.04 nmol/mg protein/min (mean +/- SEM). Troleandomycin (40 mumol/L) inhibited hydroxylamine formation at 100 mumol/L dapsone by 50%; diethyldithiocarbamate (150 mumol/L) and tolbutamide (400 mumol/L) inhibited at 5 mumol/L dapsone by 50% and 20%, respectively, suggesting that the low-affinity isozyme is CYP3A4 and the high-affinity isozymes are 2E1 and 2C. Disulfiram, 500 mg, 18 hours before a 100 mg oral dose of dapsone in healthy volunteers, diminished area under the hydroxylamine plasma concentration-time curve by 65%, apparent formation clearance of the hydroxylamine by 71%, and clearance of dapsone by 26%. Disulfiram produced a 78% lower concentration of methemoglobin 8 hours after dapsone.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle 98195, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Mitra
authors.forename: K E
authors.initials: KE
authors.lastname: Thummel
authors.forename: T F
authors.initials: TF
authors.lastname: Kalhorn
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: J D
authors.initials: JD
authors.lastname: Unadkat
authors.forename: J T
authors.initials: JT
authors.lastname: Slattery
mesh_terms: D000328:Adult; D000427:Alcohol Deterrents / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003622:Dapsone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D004221:Disulfiram / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007917:Leprostatic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D000427:Alcohol Deterrents; D000900:Anti-Bacterial Agents; D007917:Leprostatic Agents; D003622:Dapsone; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; C018209:4-amino-4'-hydroxylaminodiphenylsulfone; D004221:Disulfiram