A PHARMACOKINETIC AND PHARMACOGENETIC STUDY OF CHEMOTHERAPEUTIC

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。长春花生物碱类、蒽环类、紫杉烷类和鬼臼毒素类是治疗血液系统和实体肿瘤的重要化疗药物。尽管如此，关于这些药物的处置和最佳剂量的信息相对较少。既往药代动力学研究已记录了大量患者间变异性，临床使用与不可预测的毒性相关。需要优化这些种类的药剂的剂量，特别是因为它们都用于治疗可治愈的恶性肿瘤，包括淋巴瘤和生殖细胞肿瘤。代谢（细胞色素P450 3A 4）和/或转运（P-糖蛋白）这些药物的酶的药物遗传学研究与药代动力学分析相结合，将更好地了解这些药物的分布。这种增加的了解将帮助我们更好地预测谁获得了过量的药物暴露，从而增加了毒性，以及那些潜在的亚治疗药物水平和潜在的不良结果从剂量不足。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The vinca alkaloids, anthracyclines, taxanes and podophyllotoxins are important classes of chemotherapeutic drugs in both hematological and solid malignancies. Despite this, there is relatively little information available regarding the disposition and optimal dosing of these agents. Prior pharmacokinetic studies have documented substantial inter-patient variability and clinical use is associated with unpredictable toxicities. It is desirable to optimize the dosing of these classes of agents especially as they are all used to treat curable malignancies including lymphomas and germ cell tumors. A pharamacogenetic study of enzymes that metabolize (cytochrome P450 3A4) and/or transport (p-glycoprotein) these agents paired with a pharmacokinetic analysis will provide a better understanding of the disposition of these agents. This increased understanding will help us better predict who gains an excess exposure to the drug and hence experience increased toxicity as well as those with potentially sub-therapeutic drug levels and potentially a poorer outcome from under-dosing.