IN-VIVO ACCUMULATION OF ETOPOSIDE IN PERIPHERAL LEUKEMIC-CELLS IN PATIENTS TREATED FOR ACUTE MYELOBLASTIC-LEUKEMIA - RELATION TO PLASMA-CONCENTRATIONS AND PROTEIN-BINDING

Since etoposide interacts with the nuclear enzyme topoisomerase II, th e drug concentrations in the malignant cells during chemotherapy may h ave clinical correlates. Plasma protein binding of etoposide is extens ive (94%) and alterations of the non-proteinbound fraction affect phar macokinetic behavior of the drug. The pharmacokinetics of etoposide wa s therefore studied in plasma, total and non-proteinbound concentratio ns, and in leukemic cells isolated from peripheral blood samples from 22 patients after the first dose of the induction treatment for acute myelocytic leukemia. Fourteen patients received 100 mg/m2 and eight pa tients 200 mg/m2 as a 1 h infusion. The mean area under the concentrat ion versus time curve AUC(0-infinity) in plasma was at the lower dose level 78.4 +/- 29.1 (mean +/- S.D.) mug/ml x h and 201.0 +/- 56.5 mug/ ml x h at the higher dose level. The fraction of non-proteinbound etop oside in plasma was 5.2 +/- 3.4 and 5.4 +/- 2.1% in the two treatment groups. AUC(0-16h) in leukemic cells was 8.4 +/- 8.7 and 22.4 +/- 12.1 mug/ml x h at the two dose levels, respectively. The cellular etoposi de concentration was 12.1 +/- 7.9 and 14.7 +/- 5.1% of the plasma conc entration at the end of the infusion. The interpatient variability in cellular drug levels was considerable and exceeded the variability in plasma concentrations. Cellular accumulation of etoposide could be imp ortant for treatment outcome.