Two-Mechanism Peak Concentration Model for Cellular Pharmacodynamics of Doxorubicin

Neoplasia: An International Journal for Oncology Research

Ardith W. El-Kareh¹  Timothy W. Secomb² 

[1] ARL-Microcirculation Division, University of Arizona, PO Box 245051, Tucson, AZ 85724-5051, USA;Department of Physiology, University of Arizona, Tucson, AZ, USA;

关键词: chemotherapy;    doxorubicin;    adriamycin;    cellular pharmacodynamics;    mathematical model;   

DOI  :  10.1593/neo.05118

来源: DOAJ

【 摘 要 】

A mathematical model is presented for the cellular uptake and cytotoxicity of the anticancer drug doxorubicin. The model assumes sigmoidal, Hill-type dependence of cell survival on drug-induced damage. Experimental evidence indicates distinct intracellular and extracellular mechanisms of doxorubicin cytotoxicity. Drug-induced damage is therefore expressed as the sum of two terms, representing the peak values over time of concentrations of intracellular and extracellular drugs. Dependence of cell kill on peak values of concentration rather than on an integral over time is consistent with observations that dose-response curves for doxorubicin converge to a single curve as exposure time is increased. Drug uptake by cells is assumed to include both saturable and unsaturable components, consistent with experimental data. Overall, the model provides better fits to in vitro cytotoxicity data than previous models. It shows how saturation of cellular uptake or binding with concentration can result in plateaus in the dose-response curve at high concentrations and short exposure, as observed experimentally in some cases. The model provides a unified framework for analyzing doxorubicin cellular pharmacokinetic and pharmacodynamic data, can be applied in mathematical models for tumor response and treatment optimization.

【 授权许可】

Unknown