9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate pharmacokinetics in plasma and tumor cells of patients with relapsed leukemia and lymphoma.
The pharmacokinetics of 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) in plasma and its biologically active 5'-triphosphate (F-ara-ATP) in leukemic cells obtained from the peripheral blood and bone marrow was evaluated in patients with hematologic malignancies subsequent to the first dose of 20-125 mg/m2 per day for 5 days of F-ara-A 5'-monophosphate (F-ara-AMP) administered as an IV bolus over 30 min. The terminal half-lives of elimination of both F-ara-A (8 h) in plasma and intracellular F-ara-ATP (15 h) were not dependent upon the dose of F-ara-AMP. The area under the concentration X time curves for F-ara-A and F-ara-ATP, on the other hand, were increased in proportion to the prodrug dose. There was a high correlation between F-ara-ATP levels in circulating leukemic cells and those in bone marrow cells aspirated at the same time. DNA-synthetic capacity of leukemic cells was inversely related to the associated F-ara-ATP concentration. A linear trend was noted when F-ara-ATP levels in pretreatment peripheral blood leukemic cells incubated with F-ara-A in vitro were compared with the amount of F-ara-A that was incorporated into nucleic acids. Finally, F-ara-ATP concentrations were three times higher in bone marrow cells from patients with lymphomatous bone marrow involvement than from those without evidence of marrow disease.
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism*; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D001088:Arabinonucleotides / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism*; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives / Q000378:metabolism* / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D001088:Arabinonucleotides; D001084:Vidarabine Phosphate; D001085:Arabinofuranosylcytosine Triphosphate; C042382:fludarabine phosphate; C034957:2-fluoro-araATP; D004247:DNA