Abstract
The aim of this study was to examine the relationship between the pharmacokinetics of daunorubicin (DNR), overexpression of P-glycoprotein (Pgp) and treatment response in acute leukaemia. Twenty-seven patients with acute leukaemia received DNR as part of induction therapy. The plasma and cellular levels of DNR and its metabolite daunorubicinol (DOL) were determined using high-performance liquid chromatography. There were no significant differences between patients who went into complete remission (12/23) compared with those who did not respond for the following pharmacokinetic parameters: DNR and DOL plasma AUC (area under the curve) and DNR plasma half-life and clearance. There was a significant difference in the cellular DNR and DOL AUC between responders and non-responders (P < 0.02). Seven patients were Pgp positive and 18 Pgp negative. There was no correlation between patient response and the presence of Pgp (P > 0.1), nor was there any correlation between the cellular concentration of DNR or DOL and Pgp (P > 0.3). To our knowledge this is the first report examining the relationship between DNR pharmacokinetics, patient response and Pgp expression. Our data indicated that acute leukaemia patients responding to chemotherapy had higher cellular DNR and DOL than non-responders; also, overexpression of Pgp appeared not to be the sole explanation for the lower cellular DNR levels as expected from in vitro studies.
Highlights
Sm_nary The aim of this study was to examine the relationship between the pharmacokinetics of daunorubicin (DNR), overexpression of P-glycoprotein (Pgp) and treatment response in acute leukaemia
There were no significant differences between patients who went into complete remission (12/23) compared with those who did not respond for the following pharmacokinetic parameters: DNR and DOL plasma area under the curve (AUC) and DNR plasma half-life and clearance
multidrug resistance (MDR) is associated with the presence of a protein called P-glycoprotein (Pgp), and it has been hypothesised that intracellular cytotoxic agents are removed from the cell via Pgp, decreasing the intracellular concentration and the effectiveness of these drugs
Summary
Twenty-seven patients with either acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL) were studied. Patients received DNR (David Bull Laboratories, Victoria, Australia) infused over a 15 min period (Table I) as part of their induction chemotherapy. For AML patients the chemotherapy protocol consisted of Ara-C 100 mg m-2 day-'. For ALL patients the Hoelzer protocol (Hoelzer et al., 1984) was used, which consisted of daily prednisolone with weekly injections of DNR 25 mg m-2 and vincristine over the first 4 weeks of induction. Response was determined according to standard criteria as follows: a complete remission (CR) was defined as a reduction of blast cells below 5% and a return to normal haematopoiesis within 4 weeks after the commencement of chemotherapy; a partial response (PR) was defined as some reduction of blasts in the original population but without adequate normal haemopoietic recovery; no response was recorded when there was no alteration or an increase in the blasts. Patients with a partial response were grouped with those patients that had no response and are termed non-responders (NRs)
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