CLINICAL TRIAL: A PHASE I PHARMACOKINETIC STUDY OF PS-341 IN PATIENTS WITH ADVAN

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 PS-341的主要消除途径是代谢。 PS-341的代谢主要由细胞色素P450亚型3A 4和2D 6介导。 主要代谢途径是脱硼，形成一种代谢产物，未观察到蛋白酶体抑制特性。 脱硼代谢物随后形成许多羟基化代谢物。PS-341的蛋白结合率约为84%。 肝功能不全在癌症患者中并不罕见。肝功能障碍患者可能会经历更多的药物暴露和许多药物的毒性。PS-450酶代谢PS-341，因此与无肝功能障碍的患者相比，肝功能障碍患者可能具有不同的药代动力学和毒性特征。基于作用机制和临床前数据，泛素-蛋白酶体抑制剂可能对许多不同类型的肿瘤有益。因此，必须在肝功能障碍患者中研究PS-341，以适当开发这种药物，这是泛素-蛋白酶体抑制剂类中的第一种药物。

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 major pathway of elimination of PS-341 is metabolism. Metabolism of PS-341 is largely mediated by the cytochrome P450 isoforms 3A4 and 2D6. The major metabolic pathway is deboronation, forming a metabolite with no observed proteasome inhibition properties. The deboronated metabolite subsequently forms a number of hydroxylated metabolites. Protein binding of PS-341 is approximately 84%. Liver dysfunction is not uncommon in cancer patients. Patients with liver dysfunction may experience greater drug exposure and toxicity from many drugs. CYP 450 enzymes metabolize PS-341, therefore patients with liver dysfunction may have different pharmacokinetic and toxicity profiles compared to patients without liver dysfunction. Based on the mechanism of action and the pre-clinical data ubiquitin-proteasome inhibitors may be beneficial in many different tumor types. It is therefore imperative that PS-341 be studied in patients with liver dysfunction for the proper development of this drug that is first in the class of ubiquitin-proteasome inhibitors.