DESIGN AND ANALYSIS OF PHARMACOKINETIC STUDIES OF SELENIUM

硒(Se)在长期的NCI中显示出预防癌症的活性 赞助的人类干预试验，每天补充200份 每天摄入不到100微克的人被给予微克 微克，与大部分美国人相似。仅限 可获得有关基线(未补充)代谢的信息 人类体内的无机或有机硒，目前尚无相关信息 任何一种形式的新陈代谢的变化都可能是由 摄入量增加了三倍。一项研究正在进行中，以提供 原型态硒的药代动力学信息：钠 亚硒酸盐和亚硒蛋氨酸(SeMet)。此信息对于以下项目是必需的 未来人类用药时间和方式的确定 审判。 综合动力学模型被用来解释研究数据。 已经假设了不同的身体池和之间的汇率 他们估计了，以及居留时间。这些模型表明 亚硒酸盐和亚硒蛋氨酸之间重要的动力学差异。 另一种模型被用来研究一个最重要的 差异，有机的再循环，而不是无机物的循环 形式。这些模型已被修改并合并为单个模型，以 更好地模拟膳食中的硒摄入量。 对分析数据的调整进行了改进，结果是 模型所基于的数据的值略有不同。 这些数据只反映了剂量中的示踪物。亚硒酸盐模型一直是 修改以排除示踪剂的身体存储，并且数据正在 重新进入和改装；现有的模型提供了足够的适应 修改后的数据。 动力学研究对预防试验的重要性一直是 进行了调查，并在全国会议上公布了结果。 与癌症预防研究处合作； 美国农业部贝尔茨维尔人类营养研究中心和康奈尔大学， 第二个为期三年的动力学研究已经设计完成，它将 包括1)为期6个月基线研究，其中无机物和 将收集有机硒，以便对上述模型进行改进； 2)为期两年，在此期间将补充200名受试者 3)第二次为期6个月的动力学研究。可能的 代谢的变化，血浆硒蛋白的分布，以及 在结肠微生物群落的组成中，产生于 长期补充硒的情况将被调查。一项研究 议定书已由外部专家组编写和审查 在硒研究、隔室模型和临床试验领域， 由NCI IRB根据其意见进行修改。AS 此协议很可能会随附对IND的请求 来自FDA的硒蛋氨酸，正在为此目的进行审查。

Selenium (Se) has shown cancer preventive activity in a long-term NCI sponsored human intervention trial in which a daily supplement of 200 micrograms was given to a population with a daily intake of less than 100 micrograms, similar to that of much of the U.S. population. Only limited information is available on the baseline (unsupplemented) metabolism of either inorganic or organic Se in humans, and no information is available on changes in metabolism of either form that would likely result from a three-fold increase in intake. A study is in progress to provide information on the pharmacokinetics of Se in its prototype forms: sodium selenite and selenomethionine (SeMet). This information is necessary for the determination of time and manner of administration in future human trials. Integrated kinetic models are being used to interpret the study data. Various body pools have been hypothesized and rates of exchange between them estimated, as well as residence times. The models indicate important kinetic differences between selenite and selenomethionine. Alternative models were used to investigate one of the most important differences, the recirculation of the organic, but not the inorganic form. The models have been modified and combined into a single model to better simulate dietary intake of selenium. A refinement in the adjustment of the analytical data resulted in slightly different values for the data on which the models are based. These data reflect only tracer in the dose. The selenite model has been modified to exclude body stores of the tracer, and the data are being reentered and refitted; the existing model provides adequate fits to the modified data. The importance of kinetic studies to prevention trials has been investigated, and the results presented in a national meeting. In collaboration with the Cancer Prevention Studies Branch; the Beltsville Human Nutrition Research Center, USDA; and Cornell University, a second kinetics study to last three years has been designed, which will include 1) a 6-month baseline study, in which data on both inorganic and organic Se will be collected to permit refinement of the above models; 2) a 2-year period in which subjects will be supplemented with 200 micrograms/d of SeMet; and 3) a second 6-month kinetics study. Possible changes in metabolism, in the distribution of plasma seleno-proteins, and in the composition of the colonic microbial community arising from long-term selenium supplementation will be investigated. A study protocol has been prepared and reviewed by an outside group of experts in the areas of Se research, compartmental modeling, and clinical trials, as by the NCI IRB and modified in accordance with their comments. As this protocol will likely accompany a request for an IND for selenomethionine from the FDA, it is being reviewed for this purpose.