Inhibition of fludarabine metabolism by arabinosylcytosine during therapy

Cancer Chemother Pharmacol. 1992;31(3):193-9. doi: 10.1007/BF00685547.

Abstract

The active 5'-triphosphate of arabinosyl-2-fluoroadenine (F-ara-ATP) increases the anabolism of arabinosylcytosine (ara-C), whereas ara-C 5'-triphosphate inhibits the phosphorylation of arabinosyl-2-fluoroadenine (F-ara-A) in human leukemia cells in vitro. These interactions have a potential impact on drug scheduling. Clinical trials of relapsed leukemia in which fludarabine (F-ara-A 5'-monophosphate) and ara-C were given in sequence provided the opportunity to evaluate the effects of ara-C infusion on two sequelae: the pharmacokinetics of F-ara-A in plasma and that of F-ara-ATP in leukemia cells. First, F-ara-A pharmacokinetics were altered by ara-C infusion. This was visualized as a transient increase in F-ara-A plasma levels during the ara-C infusion that was given 4 h after fludarabine. The perturbation in F-ara-A plasma levels was dependent on the dose ara-C. Second, peak F-ara-ATP concentrations were lower in leukemia cells of patients who received ara-C in addition to fludarabine as compared with those who received fludarabine alone. The terminal half-life of F-ara-A in plasma and the half-life of intracellular F-ara-ATP were reduced after the ara-C infusion in a concentration-dependent manner. Studies using purified deoxycytidine kinase support the conclusion that the increase in plasma levels of F-ara-A is in part the result of an effective competition by ara-C for phosphorylation by this enzyme, leading to a perturbation of the pharmacokinetics of intracellular F-ara-ATP.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / antagonists & inhibitors*
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Arabinonucleotides / pharmacokinetics
  • Cytarabine / administration & dosage
  • Cytarabine / pharmacokinetics
  • Cytarabine / pharmacology*
  • Deoxycytidine Kinase / metabolism
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Phosphorylation
  • Time Factors
  • Vidarabine / administration & dosage
  • Vidarabine / analogs & derivatives*
  • Vidarabine / antagonists & inhibitors
  • Vidarabine / pharmacokinetics

Substances

  • Antineoplastic Agents
  • Arabinonucleotides
  • Cytarabine
  • 2-fluoro-araATP
  • Deoxycytidine Kinase
  • Vidarabine
  • fludarabine