The objective of this project is to improve the dose and schedule of cancer chemotherapeutic agents through the understanding of the pharmacology of the drugs studied. Absorption, transport, disposition, metabolism, excretion, and pharmacokinetics of clinically established and phase I-II drugs will be studied. Biochemical microbiological, radioimmunological, and high performance liquid chromatograhic techniques will be used to analyze drug concentration in patients' plasma, urine, stool, CSF, bile, and/or tissues following drug administration. Radioimmunoassays will be developed for drugs. High performance liquid chromatography will be adapted or developed and the two methods will be compared. Where necessary and appropriate, pre-clinical pharmacology will be performed in mice, rats, and dogs with particular emphasis on tissue drug distribution and biliary excretion. The knowledge derived from the pre-clinical studies will be used to develop more rational dose-schedules for the drugs involved. In addition, the clinical pharmacokinetics information obtained will be correlated with patients' renal and hepatic functions and toxicities of the drugs. Appropriate modifications of dose-schedule may further be necessary for patients with abnormal functions. With the information obtained, effective drug regimens can be designed while toxicities can be minimized.
