KINETIC-ANALYSIS OF TISSUE DISTRIBUTION OF DOXORUBICIN INCORPORATED IN LIPOSOMES IN RATS .2.

The objective of this study is to perform kinetic modelling of the tis sue distribution of doxorubicin encapsulated into liposomes (L-DXR), e specially to the heart and liver. The release process of doxorubicin ( DXR) from liposomes in blood was quantified by a release clearance. Th is parameter defines a release rate of DXR based on the concentration of L-DXR in blood and was estimated from kinetic modelling of DXR dist ribution to the heart after L-DXR administration. The distribution of free DXR to the heart was modelled separately. The experimental data f or 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 DX R concentration in blood between free and liposomal administration. Th e area under the DXR curve in the heart was reduced by approximately o ne third from that for the first two hours after DXR administration by liposomal encapsulation, which could be the reason for reduced cardia c toxicity. In our previous report, the distribution of L-DXR to the l iver was shown to be explained by a sequentially linked two-compartmen t model with efflux process. The validity of this efflux model was exa mined in this study by a repeated dose study. The apparent uptake clea rance decreased with time and showed a second peak after the repeated dose, which justified the efflux model. These kinetic analyses give qu antitative understanding of the effect of liposomal encapsulation on t he tissue distribution of DXR.