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 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.
Demant
E J
EJ
Department of Medical Biochemistry and Genetics, The Panum Institute, University of Copenhagen, Denmark.
Friche
E
E
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000473:pathology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005947:Glucose / Q000494:pharmacology; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D012995:Solubility; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D012709:Serum Albumin; D005947:Glucose