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 theDNR naturally resistant B16 melanoma and in theDNR 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 SO (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.
KeywordsDaunorubicin daunorubicinol DNR DNR-OH pharrnacokinetics cytotoxicity P388 B16 MTT tritiated thymidine screening anticancer drags
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- 1.Dubois J., Hanocq M., Atassi G. (1987): Determination of Doxorubicin, Daunorubicin and some of their metabolites in mouse plasma by high-performance reversed-phase liquid chromatography with amperometric detection. Anal. Lett., 20, 1611–1634.Google Scholar
- 5.Arnould R. Dubois J., Abi Khalil F., et al. (1989): Comparison of two cytotoxicity assays — tetrazolium derivative reduction (MTT) and tritiated thymidine uptake — on three malignant mouse cell lines using chemotherapeutic agents and investigational drugs. Anticancer Res., 9, 6.Google Scholar
- 6.Ritschel W.A. (1982): Handbook of Basic Pharmacokinetics, 2nd edn. Hamilton, Drug Intelligence Publications Inc.Google Scholar
- 8.Silliman R. (1969): Comparison between Gompertz and Von Bertalanffy curves for expressing growth in weight of fishes. J. Fish Res. Bd. Can., 26, 161–165.Google Scholar
- 12.Norman H. (1975): Statistical Package for the Social Sciences. McGraw-Hill.Google Scholar
- 14.NCI data: Personal information from Dr G. Atassi.Google Scholar