Pharmacokinetics of anthracyclines.

Abstract

The plasma pharmacokinetics of the two commonly used anthracyclines doxorubicin and 4'epi-doxorubicin have been studied by reversed phase liquid chromatography with photometric detection. After intravenous administration the plasma pharmacokinetics of doxorubicin and 4'epi-doxorubicin are characterized by the three compartment open model. Typically, the half-life time of the alpha-phase is 3-5 min and the terminal half-life time in the order 20-30 h. An almost 10-fold inter-individual variation of the dose normalized area under the plasma concentration time curve (AUC/mg/m2) has been observed, underlining the need for an individualization of the dose. The chemical structures of doxorubicin and 4'epi-doxorubicin are very similar. Comparative pharmacokinetic studies were carried out by simultaneous administration of the drugs using a highly selective analytical technique. By this approach it was possible to reduce the influence by the large intra- and inter-individual pharmacokinetic variations. The values of AUC and Cmax were on the average 1.6 and 1.2 times larger for doxorubicin than for 4'epi-doxorubicin. Side effects, reported to be related to the maximum plasma concentration (Cmax), include cardiac toxicity, nausea and vomiting, while the antitumour effect has been associated with the area under the plasma concentration time curve (AUC). A 10-fold decrease of Cmax without a decrease of AUC was observed when doxorubicin was administered as a 4-h infusion as compared to an intravenous bolus injection. A further increase of the administration time had only a minor effect on Cmax. Intrahepatic administration of doxorubicin reduced the values of AUC and Cmax by 1.5 and 1.7 (mean values) respectively. The combination of doxorubicin and 4'epi-doxorubicin with biodegradable starch microspheres (Spherex) resulted in a further decrease of Cmax, while AUC was unaffected. The observed increase of the mean residence time (MRT) supports the assumption of an increased drug exposure of the tumour caused by Spherex.