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。 PS-341清除的主要途径是代谢。PS-341的代谢主要受细胞色素P450亚型3A4和2D6的调节。主要的代谢途径是去离子化，形成一种没有观察到的蛋白酶体抑制特性的代谢物。脱溴代谢物随后形成许多羟化代谢物。PS-341的蛋白结合率约为84%。 肝功能障碍在癌症患者中并不少见。肝功能障碍的患者可能会经历更大的药物暴露和许多药物的毒性。CYP450酶代谢PS-341，因此与无肝功能障碍的患者相比，有肝功能障碍的患者可能具有不同的药代动力学和毒性特征。根据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，必须研究PS-341在肝功能障碍患者中的作用，以便正确开发这种第一类泛素-蛋白酶体抑制剂。

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.