Transport in Liver Slices

Mechanisms of drug uptake in liver slices were studied in vitro as early as in 1963 by Schanker and Solomon [89]. The results obtained in these experiments are still valuable and show that the influence of temperature, anoxia, metabolic inhibitors and substrate inhibition can be successfully studied in this preparation. However, as mentioned before, at that time the preparation of reproducible precision-cut slices was not feasible. Therefore, the slice incubation technique was virtually abandoned in transport studies after the introduction of the successful isolation of rat hepatocytes. 

In order to investigate the possibilities and limitations of the use of precision-cut liver slices prepared with a mechanical sheer in drug transport studies, different aspects of the mechanism of uptake of several classes of drugs in human and rat liver slices were investigated in our laboratory. Four model compounds which enter hepatocytes via entirely differ- 

12 Use ofHurrmn Tissue Slices in Drug Targeting Research 

Digoxin uptake into rat hver shces showed a temperature-dependent component, compatible with the involvement of carrier-mediated uptake mechanisms. Quinine markedly inhibited the uptake of digoxin, in contrast to its diastereomer quinidine, which only slightly inhibited the digoxin uptake in rat liver slices. This stereoselective inhibition is in line with results obtained in isolated rat hepatocytes and isolated perfused rat hvers [90,91]. These results were also found after cryopreservation of the slices, indicating that carrier-specific phenomena can be studied after cryopreservation [92]. 

From these results it can be concluded that liver slices are a powerful tool for studying the mechanisms and specificity of carrier-mediated uptake of drugs and drug interactions which occur at the transport level. 

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