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Kinetics of anthracycline accumulation in multidrug-resistant tumor cells: relationship to drug lipophilicity and serum albumin binding.

Biochemical Pharmacology

Animals, Tumor Cells, Cultured, Solubility, metabolism, Serum Albumin, Protein Binding, pharmacology, Glucose, Drug Resistance, Neoplasm, Drug Resistance, Multiple, pathology, drug therapy, Carcinoma, Ehrlich Tumor, pharmacokinetics, chemistry, Antibiotics, Antineoplastic

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      A multidrug-resistant Ehrlich ascites tumor cell line (EHR2/DNR+) was used to examine the membrane transport kinetics of lipophilic anthracycline derivatives in the presence of serum albumin. We present a model for theoretical data analysis with consideration of drug-albumin complex formation. For a set of five derivatives (doxorubicin, daunorubicin, 4-demethoxydaunorubicin, 4'-deoxy-4'-iododoxorubicin, and 13-dihydro-4'-deoxy-4'-iododoxorubicin), data were given on the rates of diffusional drug uptake, and membrane permeability coefficients of the noncharged 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 effect of serum albumin could be accounted for by the altered distribution between free and protein-bound drug molecules in the bulk aqueous medium. A good fit of theoretical accumulation curves to the experimental data was obtained. It was concluded that a mathematical simulation method makes it possible to predict the uptake characteristics of lipophilic anthracycline compounds into tumor cells under serum conditions.

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