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

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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.