A PHARMACOKINETIC AND PHARMACOGENETIC STUDY OF CHEMOTHERAPEUTIC

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 长春花碱、蒽环类、紫杉烷类和鬼臼毒素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。以前的药代动力学研究已经记录了患者之间的巨大变异性，临床使用与不可预测的毒性有关。优化这些药物的剂量是可取的，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。对代谢这些制剂的酶(细胞色素P450 3A4)和/或运输(P-糖蛋白)的药物遗传学研究，结合药代动力学分析，将提供对这些制剂处置的更好理解。这种理解的增加将有助于我们更好地预测谁获得了过量的药物暴露，从而经历了毒性的增加，以及那些潜在的亚治疗药物水平和可能因剂量不足而导致的更差的结果。

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 podophylotoxins 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 pharmacogenetic 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.