This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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