Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo.
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.
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Related Subject Headings
- Troleandomycin
- Pharmacology & Pharmacy
- Oxidoreductases, N-Demethylating
- Microsomes, Liver
- Male
- Leprostatic Agents
- Hydroxylation
- Humans
- Female
- Drug Interactions
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Troleandomycin
- Pharmacology & Pharmacy
- Oxidoreductases, N-Demethylating
- Microsomes, Liver
- Male
- Leprostatic Agents
- Hydroxylation
- Humans
- Female
- Drug Interactions