The importance of the cellular pharmacokinetics of
cytarabine triphosphate (
ara-CTP) with regard to therapeutic efficacy is well established. In vitro and in vivo monitoring of pharmacokinetic parameters of leukemic blast cells were initiated in order to contribute to the pharmacological basis of optimal
ara-C treatment strategies. Peripheral or bone marrow blast cells from 66 leukemic patients [51
acute myelogenous leukemia (ALL), 15
acute lymphoblastic leukemia (AML) were separated and incubated with
ara-C for 1 hour and in
ara-C-free medium for another 3 hours, and the intracellular formation and retention of
ara-CTP was measured. In eight children who received continuous
ara-C infusion for induction treatment, the
ara-CTP concentration in circulating blast cells was monitored in vivo. The in vitro values observed in this assay corresponded to the cellular levels monitored in vivo. The
ara-CTP retention differed clearly among the individual groups, as classified by immunophenotype at the time of the initial diagnosis: non-
T-ALL 67+/-25% (x+/-SD, n=33),
T-ALL 37+/-15% (n=8), and AML 34+/-18% (n=14). The difference in
ara-CTP retention between non-
T-All and AML (P<0.05) as well as
T-ALL (P<0.05) was significant. There was a tendency toward lower
ara-CTP retention in relapsed as compared with newly diagnosed ALL, but the difference was not significant. The maximal accumulation of
ara-CTP (after 1 hour incubation) was comparable in AML,
T-ALL, non-
T-ALL, and blast cells from children in relapse. The observed similarity of cellular accumulation in all groups and the significantly more rapid decrease in
T-ALL and AML provide the pharmacokinetic rationale supporting the prolonged infusion duration for
ara-C in these subgroups as an alternative to the intensification by high-dose
ara-C schedules with short-term infusion.