Kinetic analysis of tissue distribution of doxorubicin incorporated in liposomes in rats (II).
The objective of this study is to perform kinetic modelling of the tissue distribution of doxorubicin encapsulated into liposomes (L-DXR), especially to the heart and liver. The release process of doxorubicin (DXR) from liposomes in blood was quantified by a release clearance. This parameter defines a release rate of DXR based on the concentration of L-DXR in blood and was estimated from kinetic modelling of DXR distribution to the heart after L-DXR administration. The distribution of free DXR to the heart was modelled separately. The experimental data for this modelling were reported previously (Harashima et al., Biopharm. Drug. Disposit., 13, 155-170 (1992)). This analysis provided a free DXR concentration profile as well as a release clearance of DXR after L-DXR administration. There was a remarkable difference in the free DXR concentration in blood between free and liposomal administration. The area under the DXR curve in the heart was reduced by approximately one third from that for the first two hours after DXR administration by liposomal encapsulation, which could be the reason for reduced cardiac toxicity. In our previous report, the distribution of L-DXR to the liver was shown to be explained by a sequentially linked two-compartment model with efflux process. The validity of this efflux model was examined in this study by a repeated dose study. The apparent uptake clearance decreased with time and showed a second peak after the repeated dose, which justified the efflux model. These kinetic analyses give quantitative understanding of the effect of liposomal encapsulation on the tissue distribution of DXR.
Harashima
H
H
University of Tokushima, Faculty of Pharmaceutical Sciences, Japan.
Midori
Y
Y
Ohshima
S
S
Yachi
K
K
Kikuchi
H
H
Kiwada
H
H
D000818:Animals; D004317:Doxorubicin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004337:Drug Carriers; D007700:Kinetics; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D008297:Male; D008433:Mathematics; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin