Journal of Clinical Oncology, Vol 6, 802-812, Copyright © 1988 by American Society of Clinical Oncology
Cellular pharmacokinetics of daunorubicin: relationships with the response to treatment in patients with acute myeloid leukemia
E Kokenberg, P Sonneveld, W Sizoo, A Hagenbeek and B Lowenberg
Department of Clinical Pharmacology, Rotterdam Radio-Therapeutic Institute, The Netherlands.
In an attempt to identify pharmacokinetic factors that determine the
response of acute myeloid leukemia (AML) patients to induction
chemotherapy, we determined the concentrations of daunorubicin (DNR) and
the main metabolite daunorubicinol (DOL) in vivo and particularly evaluated
the concentrations in blood and bone marrow nucleated cells. Cell
measurements were obtained in 37 evaluable patients during their first
remission induction treatment with DNR and cytarabine (ara-C) and directly
compared with the plasma distribution kinetics of DNR. We show that (1)
plasma DNR concentrations do not correlate with DNR concentrations in bone
marrow nucleated cells; but (2) plasma area under the curve (AUC) values of
DNR correlate inversely (P less than .01) with AUC values of DNR in WBCs;
(3) concentrations of DNR in WBCs correlate positively (P less than .01)
with DNR concentrations in bone marrow nucleated cells; and (4) the
concentrations of DNR in WBCs show a negative correlation (P less than .01)
with the numbers of peripheral blast cells at diagnosis. We then tested
whether the pharmacokinetic parameters had predictive value for the
clinical outcome of therapy, but none of the plasma levels or WBC and bone
marrow concentrations of DNR predicted treatment outcome. The inverse
correlation between the concentrations of DNR in WBC and the numbers of
peripheral blast cells suggests that the effective DNR concentrations
achieved intracellularly are mainly a function of the tumor load so that
lesser amounts of DNR accumulate intracellularly when the AML cell numbers
in blood are higher.
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