DESIGN AND ANALYSIS OF PHARMACOKINETIC STUDIES OF SELENIUM

硒药代动力学研究的设计与分析

• 批准号: 2571494
• 负责人: B H PATTERSON
• 金额: --
• 依托单位: DIVISION OF CANCER PREVENTION AND CONTROL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2571494
• 关键词: cancer prevention; chemoprevention; clinical research; computer simulation; dietary trace element; dosage; human subject; metal metabolism; model design /development; nutrient bioavailability; nutrition aspect of cancer; nutrition related tag; pharmacokinetics; selenium; statistics /biometry

Selenium (Se) has shown cancer preventive activity in a long-term NCI sponsored human intervention trial in which a daily supplement of 200 mg was given to a population with a daily intake of less than 100 mg, 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. Model parameters have been reestimated for the selenite model, taking into account body stores of tracer present at the time the dose was given in the pharmacokinetics study and of tracer present in the diet. The introduction of tracer extraneous to the dose resulted in substantial changes to many model parameters. Estimates of body stores and of half-lives exceed previous estimates. These results were presented at an international Se symposium. 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 mg/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.

硒（Se）在癌症预防中显示出活性。 NCI赞助的长期人类干预试验， 每天补充200毫克的人群， 每日摄入量低于100毫克，与许多 美国人口。 只有有限的信息是 在基线（未补充）代谢时可用 无论是无机或有机硒在人体内，没有 可获得关于代谢变化的信息， 这可能是由于三倍的增长， 摄入 目前正在进行一项研究， 硒的原型形式：钠的药代动力学 亚硒酸盐和硒代蛋氨酸（SeMet）。 该信息 为确定时间和方式所必需的 在未来的人体试验中。 综合动力学模型被用来解释 研究数据。 各种尸体池已经被假设， 它们之间的汇率估计，以及 停留时间。 该模型表明重要的动力学 亚硒酸盐和硒代蛋氨酸的区别。 替代模型被用来调查一个最 重要的区别是，有机物的再循环， 而不是无机形式。 模型已经被修改了 并结合成一个单一的模型，以更好地模拟饮食 硒的摄入量。 模型参数已重新估计亚硒酸盐 模型，考虑到身体储存的示踪剂， 药代动力学研究中的给药时间 和饮食中存在的示踪剂。 引入 剂量无关的示踪剂导致大量的 改变了许多模型参数。 人体储存量的估计 和半衰期超过先前的估计。 这些结果 在国际硒研讨会上发表。 与癌症预防研究分支合作; 美国农业部贝尔茨维尔人类营养研究中心;以及 康奈尔大学，第二次动力学研究，以最后三个 设计了一个为期6年的项目，其中包括1）6个月的 基线研究，其中无机和有机的数据 将收集Se以改进上述内容 模型; 2）受试者将在2年内 补充200 mg/d的SeMet;和3）第二次 6-月动力学研究。 代谢可能发生的变化， 血浆硒蛋白的分布和 结肠微生物群落的组成， 将研究长期的硒补充。