Pharmacokinetics of daunorubicin and daunorubicinol in plasma, P388 and B16 tumours. Comparison with in vitro cytotoxicity data

Pharmacokinetics of daunorubicin and daunorubicinol in plasma, P388 and B16 tumours. Comparison with in vitro cytotoxicity data

The comparison of pharmacokinetics of DNR in mouse plasma, in the DNR naturally resistant B16 melanoma and in the DNR naturally sensitive P388 leukemia showed that there is no direct correlation between total concentrations of this drug in tumours and the sensitivity resistance of these tissues. A f...

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Bibliographic Details
Published in:European journal of drug metabolism and pharmacokinetics Vol. 16; no. 2; pp. 119 - 127
Main Authors: DUBOIS, J, HANOCQ, M, ATASSI, G, ARNOULD, R, ABIDHALIL, F
Format: Journal Article
Language:English
Published: Genève Médecine et hygiène 01-04-1991
Subjects:
Analysis of Variance
Animals
Antineoplastic agents
Biological and medical sciences
Cell Survival - drug effects
Daunorubicin - analogs & derivatives
Daunorubicin - blood
Daunorubicin - pharmacokinetics
Daunorubicin - pharmacology
General aspects
Leukemia P388 - metabolism
Medical sciences
Melanoma, Experimental - metabolism
Mice
Pharmacology. Drug treatments
Tumor Cells, Cultured - drug effects
Antineoplastic agent
Intravenous administration
Metabolite
Rodentia
P388-Leukemia
Cytotoxicity
Malignant hemopathy
Malignant tumor
In vitro
Blood plasma
Vertebrata
Mammalia
Mouse
Animal
B16-Melanoma
Tumor
Anthracyclins
Pharmacokinetics
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Summary:The comparison of pharmacokinetics of DNR in mouse plasma, in the DNR naturally resistant B16 melanoma and in the DNR naturally sensitive P388 leukemia showed that there is no direct correlation between total concentrations of this drug in tumours and the sensitivity resistance of these tissues. A finding which demonstrates the inadequacy of distribution models to select new potential anticancer drugs. Cytotoxicity of DNR and its metabolites to B16 melanoma and P388 leukemia cell lines were determined in vitro. Calculated inhibitory concentrations 50 (IC50) were compared to maximal concentrations determined by pharmacokinetic studies. In all cases in vitro IC50 were lower than Cmax values. Moreover, resistant cells in vivo were found to be sensitive to DNR and metabolites when they are propagated in vitro. Tissue concentrations, as well as in vitro data, were fitted to appropriate models by an original program (FADHA) which uses the simplex method to minimize a non-linear cost function. Best fit models were chosen by statistical criteria.
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ISSN:0378-7966
2107-0180
DOI:10.1007/BF03189948