Inhibition of fludarabine metabolism by arabinosylcytosine during therapy |
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Authors: | Annette Kemena Varsha Gandhi Donna S Shewach Michael Keating William Plunkett |
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Institution: | (1) Department of Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 52, 77030 Houston, TX, USA;(2) The University of Michigan Medical Center, 48109 Ann Arbor, MI, USA |
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Abstract: | Summary 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 of 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.Abbreviations ara-C
9- -d-arabinofuranosylcytosine
- ara-CTP
9- -d-arabinofuranosylcytosine 5 -triphosphate
- AUC
area under the concentration-time curve
- AUCp
inerease in the AUC caused by perturbation
- CLL
chronic lymphocytic leukemia
- dCyd kinase
deoxycytidine kinase
- F-ara-A
9- -d-arabinofuranosyl-2-fluoroadenine 5
- fludarabine
F-ara-AMP, 9- -d-arabinofuranosyl-2-fluoroadenine 5 -monophosphate
- F-ara-ATP
9- -d-arabinofuranosyl-2-fluoroadenine 5 -triphosphate
-
t
1/2
half-life of elimination
This work was supported in part by grants CA32839, CA46452, CA53311, and CA57629 from the National Cancer Institute, Department of Health and Human Services, by the German Research Association (DFG), and by a contract from Berlex Laboratories, Inc. |
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