Wonku Kang1, Michael Weiss. 1. Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, 06097 Halle, Germany.
Abstract
PURPOSE: Little is known of how anthracyclines are transported into the heart. Our previous kinetic study suggested saturable myocardial uptake of idarubicin. This study sought to determine the effects of temperature reduction and of doxorubicin coadministration on the transport process. METHODS: In Langendorff-perfused rat hearts, a 0.5 mg dose of idarubicin was infused over 10 min. The outflow concentration-time curve as well as the residual amounts in cardiac tissue of idarubicin and its active metabolite idarubicinol were measured after temperature reduction (from 37 degrees C to 30 degrees C) and in the presence of doxorubicin (20 microM) in the perfusate. The outflow concentration-time profile of idarubicin was analyzed by a four-compartment model and simultaneous nonlinear regression. RESULTS: Doxorubicin significantly inhibited the Michaelis-Menten-like uptake process of idarubicin in the heart (50% decrease in Vmax), leading to a decreased net tissue uptake of idarubicin. Kinetic analysis of sensitivity to temperature reduction revealed a 2.6-fold increase in KM; however, this inhibition of idarubicin uptake was counterbalanced by a decrease in efflux rate. CONCLUSIONS: These data confirm the existence of a saturable myocardial uptake mechanism for idarubicin and might provide useful information for optimizing anthracycline dosage regiments.
PURPOSE: Little is known of how anthracyclines are transported into the heart. Our previous kinetic study suggested saturable myocardial uptake of idarubicin. This study sought to determine the effects of temperature reduction and of doxorubicin coadministration on the transport process. METHODS: In Langendorff-perfused rat hearts, a 0.5 mg dose of idarubicin was infused over 10 min. The outflow concentration-time curve as well as the residual amounts in cardiac tissue of idarubicin and its active metabolite idarubicinol were measured after temperature reduction (from 37 degrees C to 30 degrees C) and in the presence of doxorubicin (20 microM) in the perfusate. The outflow concentration-time profile of idarubicin was analyzed by a four-compartment model and simultaneous nonlinear regression. RESULTS:Doxorubicin significantly inhibited the Michaelis-Menten-like uptake process of idarubicin in the heart (50% decrease in Vmax), leading to a decreased net tissue uptake of idarubicin. Kinetic analysis of sensitivity to temperature reduction revealed a 2.6-fold increase in KM; however, this inhibition of idarubicin uptake was counterbalanced by a decrease in efflux rate. CONCLUSIONS: These data confirm the existence of a saturable myocardial uptake mechanism for idarubicin and might provide useful information for optimizing anthracycline dosage regiments.