P-glycoprotein inhibitor valspodar (PSC 833) increases the intracellular concentrations of daunorubicin in vivo in patients with p-glycoprotein-positive acute myeloid leukemia

Purpose: The aim of the present study was to evaluate the effect of the cyc losporine derivative valspodar (PSC 833; Amdray, Novartis Pharma, Basel, Sw itzerland) on the concentration of daunorubicin (dnr) in leukemic blast cel ls in vivo during treatment. Patients and Methods: Ten patients with acute myeloid leukemia (AML) were i ncluded. Leukemic cells from seven of the patients were P-glycoprotein (Pgp ]-positive. dnr 100 mg/m(2) was given as a continuous infusion over 72 hour s. After 24 hours, a loading dose of valspodar was given, followed by a 36- hour infusion of 10 mg/kg per 24 hours. Blood samples were drawn at regular intervals, and concentrations of dnr and its main metabolite, daunorubicin ol, in plasma and isolated leukemic cells were determined by high-pressure liquid chromatography. Results: The mean dnr concentrations in leukemic cells 24 hours after the s tart of infusion (before valspodar) were 18.8 mu mol/L in Pgp-negative samp les and 13.5 mu mol/L in Pgp-positive samples. After 8 hours of valspodar i nfusion, these values were 25.8 and 24.0 mu mol/L, respectively. The effect of valspodar was evaluated from the ratio of the area under the curve (AUC ) for dnr concentration versus time in leukemic cells to the AUC for dnr co ncentration against time in the plasma. For the seven patients with pgp-pos itive leukemia, the mean ratio increased by 52%, from 545 on day 1 to 830 o n day 2 (P < .05) when valspodar was given. In the three patients with Pgp- negative leukemia, no significant difference wets observed. Conclusion: These results strongly suggest that valspodar, by interacting w ith Pgp, can increase the cellular uptake of dnr in leukemic blasts in vivo . (C) 2000 by American Society of Clinical Oncology.