Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo

Article abstract of DOI:10.1016/0009-9236(95)90176-0

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 μmol/L) inhibited hydroxylamine formation at 100 μmol/L dapsone by 50%; diethyldithiocarbamate (150 μmol/L) and tolbutamide (400 μmol/L) inhibited at 5 μmol/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.