A PHARMACOKINETIC AND PHARMACOGENETIC STUDY OF CHEMOTHERAPEUTIC

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。长春花生物碱、蒽环类药物、紫杉烷和足臼毒素是血液和实体恶性肿瘤化疗药物的重要类别。尽管如此，关于这些药物的处置和最佳剂量的可用信息相对较少。先前的药代动力学研究已经证明了大量的患者间差异和临床使用与不可预测的毒性有关。需要优化这类药物的剂量，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 3A4）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处置。这种了解的增加将帮助我们更好地预测哪些人会过量接触药物，从而经历毒性增加，以及那些药物水平可能低于治疗水平、剂量不足可能导致预后较差的人。

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.