title: Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy.
abstract: OBJECTIVE
  A protocol was designed to test the hypothesis that fludarabine infusion before arabinosylcytosine (cytarabine [ara-C]) would increase the accumulation of the active metabolite ara-C triphosphate (ara-CTP) in acute myelogenous leukemia (AML) blasts during therapy.
  
  
  METHODS
  Patients (n = 5) received 1 g/m2 of ara-C infused intravenously (IV) for 2 hours, followed at 20 hours by 30 mg/m2 of fludarabine for 30 minutes. At 24 hours, another identical dose of ara-C was infused. To determine the optimal duration of ara-C infusion following fludarabine, five additional patients were treated on an amended protocol in which the ara-C infusion was extended to 3 g/m2 infused over 6 hours.
  
  
  RESULTS
  Comparison of ara-CTP pharmacokinetics in circulating AML cells demonstrated that the area under the curve (AUC) of ara-CTP increased significantly (median, 1.8-fold; range, 1.6 to 2.4; P = .004) after fludarabine infusion. Neither the median plasma ara-C concentrations, the levels of its deamination product arabinosyluracil, nor the rate of ara-CTP elimination from circulating blasts was affected by fludarabine infusion. However, the rate of ara-CTP accumulation by AML cells was increased by a median of 2.0-fold (range, 1.8 to 2.2; P = .001) after fludarabine; the peak occurred within 1 hour of the end of the infusion. In vitro incubation of these cells with arabinosyl-2-fluoroadenine (F-ara-A) before ara-C also produced a median 1.7-fold increase in the ara-CTP accumulation rate. Pharmacology studies in patients receiving 6-hour infusions of ara-C demonstrated that the rate of ara-CTP accumulation was potentiated beyond 2 hours, but not for 6 hours.
  
  
  CONCLUSIONS
  Infusion of fludarabine before ara-C augments the rate of ara-CTP synthesis in circulating AML blasts during therapy. Evaluation of 6-hour ara-C infusions demonstrated that potentiation of ara-CTP synthesis is maximal up to 4 hours in most patients; this pharmacologically optimized regimen should be considered for combination with other antileukemia drugs.
authors.affiliation: Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
authors.forename: V
authors.initials: V
authors.lastname: Gandhi
authors.forename: E
authors.initials: E
authors.lastname: Estey
authors.forename: M J
authors.initials: MJ
authors.lastname: Keating
authors.forename: W
authors.initials: W
authors.lastname: Plunkett
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy*; D008875:Middle Aged; D012008:Recurrence; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D003561:Cytarabine; D014740:Vidarabine; C024352:fludarabine