PHARMACOKINETIC STUDIES OF INTRACELLULAR ZDV IN CHILDREN

齐多夫定（ZDV）的儿科临床试验显示， 治疗人类免疫缺陷病毒（HIV）的有效性 疾病显示了临床、病毒学和免疫学特征 在治疗过程中有所改善。不幸的是，随后的研究 在儿科人群中已经很少， 尚未确定ZDV血浆浓度和临床疗效。 这种关系的缺乏可能是由于ZDV需要被 代谢为ZDV-三磷酸（ZDV-TP）变得活跃， 酶促过程的活化步骤取决于不 与ZDV血浆浓度相关。其中一些因素包括， 竞争病毒的内源核苷酸浓度 ZDV-TP的复制和ZDV代谢产物的形成和活化 包括靶细胞的激活状态。此外，我们认为， 考虑到患者间酶促反应的变异性， ZDV和AMT的激活过程，可能血浆ZDV 浓度与毒性和/或抗病毒性关系不大 活动因此，ZDV代谢物的细胞内测量可以 在临床疗效/毒性方面提供了比 血浆ZDV浓度。 细胞内抗逆转录病毒抗体检测方法的建立 核苷酸在儿科临床环境中的应用至关重要， 了解这些药物的药理机制， 人口这一理解将对当前的 儿童艾滋病毒感染管理战略;然而， 有资料可查。检查ZDV程度的研究 成年人中的磷酸化水平在其目前的 格式，因为它们需要15至75 mL的 血这种大血量阻碍了进行PK的可能性 在儿科人群中进行分析。因此，需要开发新的 可以测量细胞内水平的分析方法 齐多夫定和其他抗逆转录病毒药物在儿科人群中的应用 使用少量血液样本。我们的长期目标是了解 抗逆转录病毒药物的基本药理学参数 在儿科人群中的治疗。 该研究项目还将提高以下可能性： 少数民族学生成为研究领域的活跃分子 促进新科学家的发展， 研究人员在波多黎各。 该研究项目的具体目标是： 1.建立新的方法来减少血液采样量， 实施ZDV磷酸化物质的药代动力学研究， 儿科人群。这些方法将来可以用来 研究其他抗逆转录病毒核苷; 2.建立磷酸化ZDV的药代动力学参数 儿科人群中的种属，如体内ZDV-TP半衰期，和 开发可用作预测PK的工具的数学模型 配置文件; 3.探讨ZDV磷酸化与 种属药理学参数和抗病毒活性， 血浆HIV RNA-PCR（Roche）; 4.为本科生、研究生和医学生提供机会， 代表性不足的少数民族学生成为积极的生物医学 这将对我们的社会产生影响。

Pediatric clinical trials with zidovudine (ZDV) have shown its effectiveness for the treatment of the Human Immunodeficiency Virus (HIV) disease . Clinical, virologic, and immunologic characteristics were shown to improve during the course of therapy. Unfortunately, subsequent studies in the pediatric population have been scarce and a relationship between ZDV plasma concentration and clinical efficacy has not been established. The lack of this relationship may be due to the fact that ZDV needs to be metabolized to ZDV-triphosphate (ZDV-TP) to become active, and the activation steps of the enzymatic processes are dependent on factors not related to ZDV plasma concentrations. Some of these factors include, the concentration of endogenous nucleotides competing for the virus replication with ZDV-TP formation and activation of ZDV metabolites including and the activation state of the target cells. Besides, considering the possibility of interpatient variability in the enzymatic activation processes o ZDV and AMT, it is likely that plasma ZDV concentration has little relationship with toxicity and/or antiviral activity. Therefore, intracellular measurements of ZDV metabolites may provide a better marker with respect to clinical efficacy/toxicity than plasma ZDV concentrations. The development of procedures to measure intracellular antiretroviral nucleotides in a pediatric clinical setting is of utmost importance to understand the pharmacological mechanisms of these drugs in this population. This understanding would have a great impact in the current strategy for management of HIV infection in children; however, no such information is available. Studies examining the extent of ZDV phosphorylation in the adult population are limited in their present format to pediatric studies, since they require between 15 to 75 mL of blood. This large blood volume hinders the possibilities to perform PK analysis in the pediatric population. Thus, there is a need to develop new analytical procedures that could measure intracellular levels of zidovudine and other antiretroviral drugs in the pediatric population using small blood volume samples. Our long term goal is to understand the basic pharmacological parameters that are involved with antiretroviral therapy in the pediatric population. This research project will also enhance the possibilities for underrepresented minority students to become active in a research area related to AIDS, promoting the development of new scientists and researchers in Puerto Rico. The specific aims of the research project are: 1. to establish new methodology to decrease blood sampling volume, for the implementation of pharmacokinetic studies of ZDV-phosphorylated species in the pediatric population. These methods could be used in the future to study other antiretroviral nucleosides; 2. to establish the pharmacokinetic parameters of ZDV phosphorylated species in a pediatric population such as, in vivo ZDV-TP half-life, and develop mathematical models that could be used as tools to predict PK profiles; 3. to probe for the existing relationships between ZDV phosphorylated species pharmacological parameters and anti viral activity as measured by plasma HIV RNA-PCR (Roche); 4. to provide an opportunity for undergraduate, graduate and medical underrepresented minority students to become active in a biomedical research area that will have an impact in our society.