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Kinetic analysis of tissue distribution of doxorubicin incorporated in liposomes in rats: I
Author(s) -
Harashima Hideyoshi,
Ohshima Shunji,
Midori Yukari,
Yachi Kiyoto,
Kikuchi Hiroshi,
Kiwada Hiroshi
Publication year - 1992
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510130302
Subject(s) - liposome , pharmacokinetics , inulin , doxorubicin , chemistry , distribution (mathematics) , endocytosis , in vivo , compartment (ship) , pharmacology , biophysics , biochemistry , medicine , biology , chemotherapy , receptor , mathematical analysis , oceanography , mathematics , microbiology and biotechnology , geology
The purpose of this study was to perform a kinetic analysis of the tissue distribution of doxorubicin (DXR) and liposomes separately after intravenous administration of DXR entrapped in liposomes in rats. Liposomes were double labeled with 14C‐DXR (L‐DXR) and 3H‐inulin (L‐INU). Blood and tissues were sampled at specified times until 120 min. Blood clearance of L‐DXR was similar to that of L‐INU. Distribution of both L‐DXR and L‐INU into the liver was parallel and extensive, while in the heart, the pattern of distribution differed between L‐DXR and L‐INU after peak concentration. Time courses of tissue concentration were explained well by dividing tissue into a shallow compartment with efflux and a deep compartment without efflux. In the liver, pharmacokinetic parameters of L‐DXR and L‐INU were similar, and the two kinetically different compartments may correspond to different uptake processes in hepatic endocytosis. In the heart, the shallow compartment was considered to correspond to the cardiac vascular space, and the intercompartmental rate constant ( k 3 ) for L‐DXR was much larger than that for L‐INU. The estimated half‐life for this process was 20 min. The half‐life for the degradation of liposomes in blood circulation was also estimated at 20 min from data on the urinary excretion of released 3H‐inulin. These results suggest that the release of DXR from liposomes may be the rate‐limiting process in the tissue distribution of DXR to the heart.