Pharmacokinetic Study on the Mechanism of Tissue Distribution of Doxorubicin: Interorgan and Interspecies Variation of Tissue-To-Plasma Partition Coefficients in Rats, Rabbits, and Guinea Pigs

doi:10.1002/jps.2600731008

Journal of Pharmaceutical Sciences

Volume 73, Issue 10, October 1984, Pages 1359-1363

https://doi.org/10.1002/jps.2600731008 Get rights and content

Abstract

The mechanism of interorgan and interspecies variations in the tissue distribution of doxorubicin was studied in rats, rabbits, and guinea pigs. The permeation properties of doxorubicin were investigated by using isolated rat erythrocytes as a model membrane. A significant dependency of the uptake rate constant on medium pH was observed, suggesting that only un-ionized doxorubicin is diffusible through the plasma membrane. The values of plasma unbound fraction (f_p) of doxorubicin were 0.344 for rats, 0.415 for rabbits, and 0.529 for guinea pigs. The tissue DNA concentrations of rats were larger than those of rabbits and smaller than those of guinea pigs in corresponding organs or tissues. An in vitro organ model that described the distribution behavior of doxorubicin in the whole body was constructed, and an equation was derived to estimate the tissue-to-plasma partition coefficients, (K_p) from in vitro experiments. The in vitro K_p values showed comparatively good agreement with the in vivo K_p values for the various organs or tissues in all three species. Doxorubicin is exclusively bound to the nuclei in the cells. The variation of the K_p values in different organs depended on the amount of nuclei per gram of tissue. The primary determinant of the interspecies variation in the K_p values was the difference in tissue DNA concentrations among rats, rabbits, and guinea pigs, and a secondary determinant was the difference in f_p values.

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Research ArticlesPharmacokinetic Study on the Mechanism of Tissue Distribution of Doxorubicin: Interorgan and Interspecies Variation of Tissue-To-Plasma Partition Coefficients in Rats, Rabbits, and Guinea Pigs

Abstract

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Biochem. Pharmacol.

J. Pharm. Sci.

J. Pharm. Sci.

Biochem. Pharmacol.

Biochem. Pharmacol.

J. Pharm. Sci.

J. Pharm. Sci.

Am. J. Obstet. Gynecol.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Cancer Res.

J. Pharmacol. Exp. Ther.

Cancer Chemother. Rep., Part 1

Research Articles
Pharmacokinetic Study on the Mechanism of Tissue Distribution of Doxorubicin: Interorgan and Interspecies Variation of Tissue-To-Plasma Partition Coefficients in Rats, Rabbits, and Guinea Pigs