May D G, Porter J A, Uetrecht J P, Wilkinson G R, Branch R A
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
Clin Pharmacol Ther. 1990 Dec;48(6):619-27. doi: 10.1038/clpt.1990.204.
The relative importance of N-hydroxylation and acetylation of dapsone to the oral clearance of dapsone (100 mg) was investigated in seven healthy volunteers. Plasma dapsone and monoacetyldapsone concentrations rose rapidly with subsequent similar monoexponential elimination. The oral clearance of dapsone was low (33 +/- 14 ml/min), with a threefold variability. Four subjects were identified as fast acetylators; however, differences in acetylation did not explain the variability in oral clearance. The cumulative urinary recoveries of dapsone and its hydroxylamine were approximately 20% of the dose. The formation clearance of hydroxylamine, which exhibited a tenfold intersubject variability, was closely associated with the oral clearance of dapsone (r = 0.96). Thus, the formation of the hydroxylamine is more important than acetylation in determining dapsone's intersubject variability in oral clearance. Variation in N-hydroxylation may have clinical consequences, because the hydroxylamine is considered to be important in dapsone-mediated toxicity.
在7名健康志愿者中研究了氨苯砜的N-羟基化和乙酰化对氨苯砜（100毫克）口服清除率的相对重要性。血浆氨苯砜和单乙酰氨苯砜浓度迅速上升，随后呈相似的单指数消除。氨苯砜的口服清除率较低（33±14毫升/分钟），具有三倍的变异性。4名受试者被确定为快速乙酰化者；然而，乙酰化的差异并不能解释口服清除率的变异性。氨苯砜及其羟胺的累积尿回收率约为给药剂量的20%。羟胺的生成清除率在受试者间表现出10倍的变异性，与氨苯砜的口服清除率密切相关（r = 0.96）。因此，在决定氨苯砜口服清除率的受试者间变异性方面，羟胺的生成比乙酰化更重要。N-羟基化的变化可能具有临床意义，因为羟胺被认为在氨苯砜介导的毒性中起重要作用。
