INFLUENCE OF FLUDARABINE ON PHARMACOKINETICS AND PHARMACODYNAMICS OF CYTARABINE - IMPLICATIONS FOR A CONTINUOUS-INFUSION SCHEDULE

Arabinosylcytosine (ara-C) is a cytotoxic agent with major activity ag ainst acute leukemias, To exert this effect, it must first be phosphor ylated to its active 5'-triphosphate, ara-CTP, which is incorporated i nto DNA. Our previous studies demonstrated that preincubation with ara binosyl-2-fluoroadenine (F-ara-A) increased the rate of ara-CTP accumu lation in leukemia cells when incubated with 10 mu M ara-C, Such conce ntrations of ara-C are readily obtained during intermittent bolus infu sions of ara-C, and clinical trials were conducted using fludarabine i n combination with 2-h infusions of intermediate-dose ara-C, During co ntinuous infusion of ara-C, however, serum ara-C levels are <10 mu M. Because the effectiveness of ara-C depends on the levels of intracellu lar ara-CTP and its incorporation into DNA, we sought to investigate t he influence of fludarabine on pharmacodynamics of ara-C at concentrat ions of ara-C achieved during continuous infusion. Using the K562 huma n leukemic cell line, we established that incubation with 30 mu M F-ar a-A was able to modulate intracellular dNTP pools and achieve maximum enhancement of ara-CTP levels at all concentrations of ara-C tested (0 .3-10.0 mu M). The relative enhancement of ara-CTP concentrations rang ed from 2.2- to 2.8-fold, Combination of F-ara-A with 1.0 and 3.0 mu M ara-C also increased the incorporation of ara-CTP into DNA, To model the influence of F-ara-A on continuous infusion ara-C, cells were incu bated with 1 mu M ara-C alone or in combination with F-ara-A. The F-ar a-A-incubated cells accumulated effective intracellular concentrations of F-ara-ATP, which resulted in greatly increased intracellular ara-C TP levels. These studies demonstrate the capacity of clinically attain able concentrations of F-ara-ATP to enhance the formation of ara-CTP a t concentrations of ara-C that are achieved during a continuous infusi on schedule. Given the important role intracellular ara-CTP concentrat ions and ara-CMP incorporation into DNA have on the ultimate cytotoxic capacity of ara-C against acute myelogenous leukemia blasts, these st udies suggest a promising pharmacological model for improving the effi cacy of the continuous infusion ara-C regimen.