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A New Assessment of In Vivo Enzyme Activities in Metbolic Disorders Using Stable Isotope Methodology

使用稳定同位素方法对代谢紊乱体内酶活性进行新评估

基本信息

批准号：
07672475
负责人：
FURUTA Takashi
金额：
$ 0.45万
依托单位：
Tokyo University of Pharmacy and Life Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

The pharmacokinetics of _L-histidine in human has been investigated to evaluate the in vivo histidine ammonia-lyase system for the conversion of _L-histidine to urocanic acid. Two healthy volunteers (subjects A and B) received a single 100-mg oral dose of _L-[3,3-^2H_2,1', 3'-^<15>N_2] histidine. Blood and urine samples were obtained over 24 hr after the administration and analyzed by stable isotope dilution mass spectrometry. The pharmacokinetic parameters were calculated based on a two-compartment model. The labeled _L-histidine in subject A (t_<1/2>=1.0hr) was eliminated approximately twice faster than that in subject B (t_<1/2>=1.9hr). The total body clearances (CL_T) were 70.0 liters/hr in subject A and 30.0 liters/hr in subject B.The low ratios of the renal clearance to the total body clearance (CL_<re>/CL_T ; 1.04% for subject A and 0.43% for subject B) indicated that most of _L-histidine was eliminated via the non-renal processes._L-Histidine was rapidly metabolized to urocanic acid. The maximum plasma concentrations of urocanic acid were 59.61 ng/ml at 30 min for subject A and 46.10 ng/ml at 60 min for subjectB.The slope of the plot of urinary excretion rate of urocanic acid vs.the plasma concentration of unchanged _L-histidine was demonstrated to reflect the metabolic clearance of _L-histidine to urocanic acid. The method of evaluating the in vivo human histidine ammonialyase activities discussed in this study offers a significant value with regard to the biochemical and clinical elucidations of the heterogeneity of histidinemia.

研究了组氨酸在人体内的药动学，评价了组氨酸解氨酶系统将组氨酸转化为尿酸的作用。两名健康志愿者（受试者A和B）接受100 mg单次口服_L-[3,3-^2H_2,1', 3'-^<15>N_2]组氨酸。给药后24小时采集血液和尿液样本，用稳定同位素稀释质谱法进行分析。采用双室模型计算药代动力学参数。受试者A （t_<1/2>=1.0hr）标记的l -组氨酸的清除速度约为受试者B （t_<1/2>=1.9hr）的2倍。受试者A和受试者B的总清除率（CL_T）分别为70.0升/小时和30.0升/小时，肾脏清除率与总清除率之比较低（CL_< 0.01 /CL_T；受试者A为1.04%，受试者B为0.43%），表明大部分l -组氨酸通过非肾脏过程被清除。l -组氨酸迅速代谢为尿酸。受试者A在30min时尿尿酸的最大血药浓度为59.61 ng/ml，受试者b在60min时尿尿酸的最大血药浓度为46.10 ng/ml。尿尿中尿尿酸排泄率与血浆中不变的l -组氨酸浓度曲线的斜率反映了l -组氨酸对尿尿酸的代谢清除率。本研究中讨论的评估人体内组氨酸氨解酶活性的方法，对于组氨酸血症异质性的生化和临床解释具有重要价值。