Mitra A K, Thummel K E, Kalhorn T F, Kharasch E D, Unadkat J D, Slattery J T
Department of Pharmaceutics, University of Washington, Seattle 98195, USA.
Clin Pharmacol Ther. 1995 Nov;58(5):556-66. 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 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.
氨苯砜毒性可能是由细胞色素P450形成羟胺代谢产物引发的。在人肝微粒体中，细胞色素P450催化的氨苯砜N-氧化动力学呈双相性，米氏常数分别为0.14±0.05和0.004±0.003 mmol/L，各自的最大反应速度分别为1.3±0.1和0.13±0.04 nmol/mg蛋白/分钟（平均值±标准误）。三乙酰竹桃霉素（40 μmol/L）在氨苯砜浓度为100 μmol/L时，抑制羟胺形成50%；二乙基二硫代氨基甲酸盐（150 μmol/L）和甲苯磺丁脲（400 μmol/L）在氨苯砜浓度为5 μmol/L时，分别抑制50%和20%，这表明低亲和力同工酶是CYP3A4，高亲和力同工酶是2E1和2C。在健康志愿者口服100 mg氨苯砜前18小时给予500 mg双硫仑，可使羟胺血浆浓度-时间曲线下面积减少65%，羟胺的表观生成清除率降低71%，氨苯砜清除率降低26%。双硫仑使氨苯砜给药8小时后高铁血红蛋白浓度降低78%。
