The Physicochemical Properties and Transmembraneous Transport of Doxorubicin

Abstract

Doxorubicin is one of our most widely used and potent drugs against human cancer. It is generally assumed that doxorubicin has to enter the cell across the plasma membrane in order to exert its therapeutic effect by interference with the function of the DNA in the cell nucleus through intercalation (1). The transport mechanism by which doxorubicin enters the cell across the rate-limiting barrier is still under debate. It has been proposed that doxorubicin is actively extruded from the cells, counteracting a facilitated diffusion transport process (a carrier-mediated transport) into the cells because 1) the cellular doxorubicin uptake increases in the presence of metabolic inhibitors, and 2) the doxorubicin transport shows saturation kinetics, self-inhibition, and substrate competition (2–4). However, a membrane-bound doxorubicin-activated ATP’ase has not yet been demonstrated. So far, doxorubicin has been demonstrated to be an inhibitor of the Na,K-activated membrane-bound ATP’ase (5). Furthermore, in order to understand the transmembraneous transport mechanism of a compound, one must demonstrate how the physicochemical characteristics of the compound in the water phases on both sides of the membrane are affected, for example, by the concentration of the compound itself, the concentration of other compounds, the temperature, and the pH. The purpose of the present paper is 1) to summarize data on some of the physicochemical properties of doxorubicin in aqueous solution, and 2) to describe how these properties apparently explain some of the features of doxorubicin transport across biological membranes.