KINETICS OF ANTHRACYCLINE ACCUMULATION IN MULTIDRUG-RESISTANT TUMOR-CELLS - RELATIONSHIP TO DRUG LIPOPHILICITY AND SERUM-ALBUMIN BINDING

A multidrug resistant Ehrlich ascites tumor cell line (EHR2/DNR+) was used to examine the membrane transport kinetics of lipophilic anthracy cline derivatives in the presence of serum albumin. We present a model for theoretical data analysis with consideration of drug-albumin comp lex formation. For a set of five derivatives (doxorubicin, daunorubici n, 4-demethoxydaunorubicin, 4'-deoxy-4'-iododoxorubicin, and 13-dihydr o-4'-deoxy-4'-iododoxorubicin), data were given on the rates of diffus ional drug uptake, and membrane permeability coefficients of the nonch arged molecules were estimated. Both the initial rates and the steady- state levels of drug uptake were found to decrease by addition of BSA at concentrations ranging from 5 to 75 mg/mL. For each drug, this effe ct of serum albumin could be accounted for by the altered distribution between free and protein-bound drug molecules in the bulk aqueous med ium. A good fit of theoretical accumulation curves to the experimental data was obtained. It was concluded that a mathematical simulation me thod makes it possible to predict the uptake characteristics of lipoph ilic anthracycline compounds into tumor cells under serum conditions. (C) 1998 Elsevier Science Inc.