Pharmacokinetics of Idarubicin: Intracellular Events and Extracellular Concentrations

Although anthracyclines have been used for decades, the pharmacokinetic requirements for optimal therapeutic efficacy (effect versus side effect) are still unclear. Obviously, a high plasma peak that occurs after bolus injection is responsible for delayed cardiotoxicity, which is one of the most serious side effects. Idarubicin is the only anthracycline that can be applied orally, which results in an altered pharmacokinetic with a long terminal half time and a low plasma peak. It is still an open question, how intercellular effects, namely the DNA binding of idarubicin and cytotoxicity, are influenced by a prolongation of application time. We performed in vitro experiments with the human promyelocytic HL-60 leukemia cell line and ex vivo experiments with AML blast cells from patients. The cytotoxicity of idarubicin is in direct and linear correlation with the amount of idarubicin bound to the DNA. However, the extracellular concentrations that are necessary to achieve the maximum DNA binding are well above the levels that are accomplished during therapy. Although a number of clinical studies have shown the efficacy of idarubicin given orally in AML therapy, the significance of the plasma peak has not yet been disclosed. The prolongation of application time in vitro for more than 90 minutes did not have a notable effect upon the induction of cell death in vitro. These experiments have been performed with the HL-60 cell line and must be put into proper perspective: AML blast cells from patients exhibit a variance of three log steps of idarubicin concentration to achieve the IC50 or the IC90.