Cellular pharmacokinetics of doxorubicin in patients with chronic lymphocytic leukemia: comparison of bolus administration and continuous infusion

Abstract

The purpose of this study was to determine whether administration of doxorubicin (DOX) as a continuous infusion or a bolus injection resulted in similar leukemic cell drug concentration in patients with refractory chronic lymphocytic leukemia (CLL). This study was carried out on five patients with refractory CLL, with DOX administered either as a bolus injection (35 mg/m2; CHOP protocol) or as a constant-rate infusion for a period of 96 h (9 mg/m2 per day; VAD protocol). The two types of drug administration were used alternatively with the same patient. Plasma and cellular DOX concentration were determined using high-performance liquid chromatography. Peak plasma DOX levels were higher after the bolus injection than after continuous administration (1509 +/- 80 ng/ml vs 11.6 +/- 1.8 ng/ml, respectively), whereas the plasma area under the curve (AUC) levels were similar. Maximum DOX cellular concentrations were 8629 +/- 2902 ng/10(9) cells (bolus injection) and 2745 +/- 673 ng/10(9) cells (96 h infusion). The cellular AUC after the bolus injection was 2.85 times greater than that observed after continuous administration. This difference was due to a higher cellular peak level followed by a relatively prolonged retention of the drug, with a loss of only 25% in the first 24 h following. These findings demonstrated that in CLL the cellular DOX exposure can be notably modified by the method of drug administration, with higher drug intracellular concentrations being achieved after bolus administration than with the infusion schedule.

Activation of the CD95 (APO-1/Fas) pathway in drug- and γ-irradiation-induced apoptosis of brain tumor cells

“…In addition to these reports our findings show that cleavage of caspases and PARP following drug treatment and g-irradiation involves activation of the CD95 system. Drug concentrations used in this study correspond to plasma levels which can be achieved in patients following chemotherapy (Muller et al, 1993;Dominici et al, 1989) indicating that our findings may be of therapeutical relevance. We previously identified stimulation of the CD95 system as one mechanism leading to apoptosis in leukemia and neuroblastoma cells in response to drug treatment (Friesen et al, 1996;Fulda et al, 1997).…”

Comparative endothelial profiling of doxorubicin and daunorubicin in cultured endothelial cells

“…Importantly, we demonstrated that doxorubicin and, to a greater extent, daunorubicin induced detrimental responses in the endothelium at clinically relevant concentrations. Indeed, the plasma concentrations of ALL patients have been determined to range from 20 nM to 2 lM for doxorubicin and 20 nM-10 lM for Daunorubicin depending on the route of drug administration (Kokenberg et al, 1988;Muller et al, 1993).…”

Multidrug resistance circumvention by a new triazinoaminopiperidine derivative S9788 in vitro: definition of the optimal schedule and comparison with verapamil

“…S9788 (6-4-[2,2-di(4-fluorophenyl)ethylamino]piperidinl-yl N,N'-dipropen-2-yl 1,3,5-triazine 2,4-diamine, bismethanesulphonate) was synthesised at the Servier Research Institute (Courbevoie, France (Lucas et al, 1993) or VRP (Ozols et al, 1987;Cairo et al, 1989 (10, 20, 30 and 60 min). Cells were washed twice in ice-cold phosphate-buffered saline (PBS), trypsinised, and the cell-associated drug concentrations were determined by high-performance liquid chromatography (HPLC) with fluorimetric detection after sonication and extraction by organic solvent as described elsewhere (Muller et al, 1993 washed, trypsinised and counted as previously described. Efflux at each time point was determined by the method described in the section on DOX accumulation.…”