Analysis of drug transport kinetics in implications for drug action

Multidrug resistance (MDR) in model systems is known to be conferred by two different integral proteins-the 170-kDa P-glycoprotein (P-gp) and the 190- kDa multidrug resistance-associated protein (MRP1)-that pump drugs out of M DR cells. The intracellular level of a drug, which influences the drug's cy totoxic effect, is a function of the amount of drug transported inside the cell (influx) and the amount of drug expelled from the cell (efflux). One p ossible pharmacological approach to overcoming drug resistance is the use o f specific inhibitors that enhance the cytotoxicity of known antineoplastic agents. Many compounds have been proven to be very efficient in inhibiting P-gp activity, but only some of them can inhibit MRP1. However, the clinic al results obtained so far by this approach have been rather disappointing. The other likely approach is based on the design and synthesis of new non- cross-resistant drugs whose physicochemical properties favor the uptake of such drug by resistant cells. Our recent studies have shown that whereas th e P-gp- and MRP1-mediated efflux of different anthracycline-based drugs may not differ considerably, their kinetics of uptake do. Thus, the high uptak e of drug by cells may lead to concentrations at the cellular target site h igh enough to achieve the needed cytotoxicity against MDR cells. Therefore, increased drug lipophilicity might be one factor in improving drug cytotox icity in MDR cells. In vitro studies have shown that idarubicin, an analogu e of daunorub cin, is more effective than daunorubicin and doxorubicin agai nst MDR tumor cell lines and that this increased effectiveness is related i n part to the increased lipophilicity of idarubicin. Other studies have als o confirmed the strong impact of lipophilicity on the uptake and retention of anthracyclines in MDR cells.