fludarabine phosphate

Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and thenphosphorylated intracellularly by deoxycytidine kinase to the active triphosphate 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotid reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted. Phase I studies in humans have demonstrated that fludarabine phosphate is rapidly converted to the active metabolite, 2-fluoro-ara-A, within minutes after intravenous infusion. Consequently, clinical pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of 25 mg 2-fluoro-ara-AMP/m2 to cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations show a moderate accumulation. During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough levels increased by a factor of about 2. The terminal half-life of 2-fluoro-ara-A was estimated asapproximately 20 hours. In vitro, plasma protein binding of fludarabine rangedbetween 19% and 29%. A correlation was noted between thedegree of absolutegranulocyte count nadir and increased area under the concentration x time cfludarabine phosphate