Comparison between the plasma and intracellular pharmacology of 1-beta-D-arabinofuranosylcytosine and 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate in patients with relapsed leukemia.
The pharmacokinetics of 1-beta-D-arabinofuranosylcytosine (ara-C) and 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) and their respective 5'-triphosphates, ara-CTP and F-ara-ATP, were compared in human plasma and circulating leukemic blasts (CLB) since initial phosphorylation of ara-C and F-ara-A is catalyzed by the same enzyme, deoxycytidine kinase. These investigations were conducted in 4 patients after the first infusion of high-dose ara-C therapy (3 g/m2 i.v. infused over 2 hr) and, following the failure of each to respond, after the initial bolus of F-ara-A monophosphate (50-100 mg/m2 i.v. over 30 min) in a subsequent treatment regimen. The median terminal rate of elimination (t1/2) of F-ara-A was 8.4 hr compared to 2.2 hr for ara-C. The median t1/2 for F-ara-ATP in CLB was 12.2 hr relative to 1.9 hr for ara-CTP. To evaluate the possibility that diminished deoxycytidine kinase was a mechanism of drug resistance, the relative area under the concentration X time curve (AUC) of the active triphosphate of each prodrug in the CLB of individuals was compared. The intracellular nucleotide AUC was normalized by dividing it by the AUC of the respective nucleoside in plasma. A value of 1.0 for the resulting ratio would be expected if the accumulation and retention of F-ara-ATP and ara-CTP were identical. In these patients, however, this ratio ranged between 0.2 and 68.2. When a similar analysis was performed in vitro using four established human leukemia cell lines, a 150-fold variation was found in the normalized nucleotide AUC ratio. Thus, the metabolic characteristics of ara-CTP in CLB of patients who fail to respond to high-dose ara-C may not predict the cellular metabolism of F-ara-ATP in the same patient at a later disease stage.
D000328:Adult; D001085:Arabinofuranosylcytosine Triphosphate / Q000493:pharmacokinetics; D001088:Arabinonucleotides / Q000493:pharmacokinetics; D003561:Cytarabine / Q000097:blood / Q000493:pharmacokinetics*; D004261:DNA Replication / Q000187:drug effects; D004341:Drug Evaluation; D005260:Female; D006207:Half-Life; D006801:Humans; D007938:Leukemia / Q000097:blood / Q000188:drug therapy*; D007951:Leukemia, Myeloid / Q000097:blood / Q000188:drug therapy; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
D001088:Arabinonucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; C034957:2-fluoro-araATP; D014740:Vidarabine; C024352:fludarabine