Pharmacokinetic Basis for an Oral Chemotherapy with Idarubicin and Etoposide: Dose-Dependent Biological Effects of Topoisomerase-II-Inhibitors

Abstract

In the treatment of hematological malignancies with idarubicin or etoposide two different pharmacological phases can be discriminated. Shortly after i.v. application, a peak with high plasma concentration can be found which lasts shorter than 3 h. As well after i.v. application as after oral application, a long phase with 10–100 fold lower concentration (through level) can be found which lasts for hours or even days. The cellular reaction upon a short exposure of topoisomerase II inhibitors at high concentration is completely different than the cellular reaction upon a long exposure of topoisomerase II inhibitors at very low concentrations. Especially the epipodophyllotoxines have a high capacity to induce cellular differentiation at these conditions which is not the case with anthracyclines. For the induction of apoptosis, a exposure-time which is longer than the cell-cycle-time of the leukemic cells seems to be much more important than especially high concentrations of topoisomerase II inhibitors.