From Plasma Kinetics to Cellular Pharmacology

This paper primarily summarizes the work done under the guidance of Dr. Bruce Chabner in 1975 and 1976. During these years I studied the role of drug concentration, duration of exposure, and endogenous metabolites in determining methotrexate (MTX) cytotoxicity to the bone marrow stem cell (CFU-C). We found that the rate of loss of CFU-C during continuous intravenous infusion of methotrexate was related to the duration of exposure until the nadir in cell count was reached at 24 hours. Depletion of nucleated cells was mitigated, probably as a result of recruitment of previously uncommitted precursor cells to CFU-C, even while the MTX infusion was continued up to 48 hours. In vitro it was shown that methotrexate and leucovorin were transported competitively in the CFU-C, which was in clear contrast with rescue agents such as thymidine and nucleoside analogs. After my training my work has continued in close contact with Dr. Chabner, while the scope of both our interests broadened to include the field of multidrug resistance (MDR). My own interest focused on functional studies in MDR.