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Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo
Author(s) -
Mitra Ashoke K.,
Thummel Kenneth E.,
Kalhorn Thomas F.,
Kharasch Evan D.,
Unadkat Jashvant D.,
Slattcry John T.
Publication year - 1995
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/0009-9236(95)90176-0
Subject(s) - dapsone , chemistry , hydroxylamine , metabolite , microsome , in vivo , pharmacology , toxicity , metabolism , biochemistry , in vitro , medicine , biology , organic chemistry , microbiology and biotechnology , dermatology
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. Clinical Pharmacology & Therapeutics (1995) 58 , 556–566; doi: