Differences in the intracellular pharmacokinetics of cytosine arabinoside (AraC) between circulating leukemic blasts and normal mononuclear blood cells.
The increasing insights into the pharmacokinetics and the metabolism of cytosine arabinoside (AraC) have improved the rationale for its application in leukemia therapy and have led to a pharmacologically directed design of antileukemic treatment. The current study aims at adding to this approach by detecting differences in the intracellular metabolism of AraC 5'-triphosphate (AraCTP) between leukemic and normal mononuclear blood cells. Measurements of intracellular AraCTP levels were complemented by determinations of plasma AraC and AraU concentrations and were performed in 32 patients with acute myeloid leukemia undergoing combination therapy including either conventional (100 mg/m2 daily) or high-dose (1.0 or 3.0 g/m2 twice daily) AraC. Plasma AraC concentration showed a linear relationship to the applied AraC dose but did not correlate with intracellular AraCTP levels. During conventional-dose AraC therapy little interpatient variation was observed in AraCTP retention times in leukemic blasts from 5 patients with t1/2 values ranging from 1.70 to 2.50 h (median 2.14 h). In all cases AraCTP levels declined rapidly after the end of the AraC infusion. Substantial differences in AraCTP retention times were revealed, however, during 3 h infusions of either 1.0 or 3.0 g/m2 AraC in leukemic blasts from 10 patients with t1/2 values between 1.60 to 7.63 h (median 2.42 h). In addition, AraCTP levels declined in only one patient by > 10% within the first hour after the end of therapy and remained constant or even increased up to 1.5-fold in a post-treatment period of 1 to 2.5 h in the other nine cases. In contrast, AraCTP retention times were relatively uniform in normal mononuclear blood cells from 11 patients with t1/2 values of 3.34 to 5.29 h (median 3.85 h). More importantly, AraCTP levels dropped by > 10% within the first hour after the end of the high-dose AraC infusion in eight of 11 cases. A post-therapeutic increase > 10% was not observed in any patient. Similar findings emerged after in vitro exposure of normal bone marrow cells from six healthy volunteers to 20 mumol/l AraC for 3 h revealing a > 10% decrease of intracellular AraCTP within the first post-treatment hour in all cases with AraCTP retention times of 2.29 to 8.63 h (median 3.20 h). These differences in AraCTP pharmacokinetics between leukemic and normal blood cells may provide the basis for a modified timing of AraC administration with the aim of selectively maintaining cytotoxic AraCTP levels in leukemic blasts while allowing an intermittent drop of AraCTP levels in normal cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Hiddemann
W
W
Department of Hematology, University of Göttingen, Germany.
Schleyer
E
E
Unterhalt
M
M
Zühlsdorf
M
M
Rolf
C
C
Reuter
C
C
Kewer
U
U
Uhrmeister
C
C
Wörmann
B
B
Büchner
T
T
D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols; D001085:Arabinofuranosylcytosine Triphosphate / Q000032:analysis / Q000378:metabolism*; D001086:Arabinofuranosyluracil / Q000097:blood / Q000493:pharmacokinetics; D003561:Cytarabine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003630:Daunorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D006801:Humans; D007951:Leukemia, Myeloid / Q000097:blood* / Q000188:drug therapy; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008228:Lymphoma, Non-Hodgkin / Q000097:blood; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood; D013866:Thioguanine / Q000008:administration & dosage
D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D001086:Arabinofuranosyluracil; D013866:Thioguanine; D003630:Daunorubicin