Veronese M E, Miners J O, Randles D, Gregov D, Birkett D J
Department of Clinical Pharmacology, School of Medicine, Flinders University of South Australia, Bedford Park, Adelaide.
Clin Pharmacol Ther. 1990 Mar;47(3):403-11. doi: 10.1038/clpt.1990.46.
The present study has validated kinetically a convenient method to measure tolbutamide hydroxylation capacity in human beings by use of urinary metabolic ratios. The known in vivo and in vitro inhibitory properties of sulfaphenazole were used to convert control phase subjects to phenotypically "poor" metabolizers of tolbutamide. Six healthy subjects were given a single 500 mg oral dose of tolbutamide with and without sulfaphenazole, 500 mg every 12 hours. Tolbutamide, hydroxytolbutamide, and carboxytolbutamide in urine were determined by newly developed HPLC procedures. Plasma tolbutamide clearance and half-life were measured, as were the metabolic ratio (hydroxytolbutamide + carboxytolbutamide/tolbutamide) in successive 6-hour urine collections. The mean tolbutamide plasma clearance decreased from 0.196 +/- 0.026 ml/min/kg without sulfaphenazole to 0.039 +/- 0.009 ml/min kg with sulfaphenazole, and the mean half-life of tolbutamide increased from 7.28 +/- 0.89 hours to 38.76 +/- 13.30 hours. The metabolic ratio determined in the 6 to 12 hour urine collection period decreased from 794.0 +/- 86.6 to 126.0 +/- 79.3, and this collection period also gave the best separation of subjects between phases. There was a good correlation between tolbutamide plasma clearance and metabolic ratio (rs = 0.853, p less than 0.01, n = 12) and between the percentage decrease in plasma tolbutamide clearance and the percentage decrease in metabolic ratio (r = 0.932, p less than 0.01, n = 6). The tolbutamide urinary metabolic ratio therefore effectively distinguishes tolbutamide hydroxylase activity in "normal" subjects and in those converted to model phenotypically "poor" metabolizers by sulfaphenazole.
本研究通过尿代谢比值从动力学角度验证了一种便捷的测量人体甲苯磺丁脲羟化能力的方法。利用已知的磺胺苯吡唑在体内和体外的抑制特性，将对照期受试者转变为甲苯磺丁脲表型上的“慢”代谢者。6名健康受试者在服用或未服用磺胺苯吡唑（每12小时500毫克）的情况下，单次口服500毫克甲苯磺丁脲。采用新开发的高效液相色谱法测定尿液中的甲苯磺丁脲、羟基甲苯磺丁脲和羧基甲苯磺丁脲。测量血浆甲苯磺丁脲清除率和半衰期，以及连续6小时尿液收集的代谢比值（羟基甲苯磺丁脲+羧基甲苯磺丁脲/甲苯磺丁脲）。甲苯磺丁脲的平均血浆清除率从未服用磺胺苯吡唑时的0.196±0.026毫升/分钟/千克降至服用磺胺苯吡唑时的0.039±0.009毫升/分钟/千克，甲苯磺丁脲的平均半衰期从7.28±0.89小时增至38.76±13.30小时。在6至12小时尿液收集期测定的代谢比值从794.0±86.6降至126.0±79.3，且该收集期也能最佳地区分各期受试者。甲苯磺丁脲血浆清除率与代谢比值之间存在良好相关性（rs = 0.853，p＜0.01，n = 12），血浆甲苯磺丁脲清除率降低百分比与代谢比值降低百分比之间也存在良好相关性（r = 0.932，p＜0.01，n = 6）。因此，甲苯磺丁脲尿代谢比值能有效区分“正常”受试者以及通过磺胺苯吡唑转变为表型“慢”代谢者模型的受试者的甲苯磺丁脲羟化酶活性。
