Drug Targeting Organ-Specific Strategies

NO x µM
80
60
40
20
*
*
12.7 Efficacy Testing of the Drug Targeting Device in the Liver 325
0
0 5 10 15 20 25
Time (hours)
Figure 12.8. NO production in rat liver slices after incubation in the absence or presence of 100 µgml –1
LPS for different time periods. The NO production is measured as nitrate/nitrite (NO x) concentrations
in the medium (µM). Control (■) and + 100 µgml –1 LPS (�). Data are expressed as mean ± SEM of four
experiments. *p < 0.005 represents a significant increase in NO production by liver slices due to
stimulation by LPS.
duction (Figure 12.9) in the liver slice model. These results show that the conjugate dexamethasone
10–HSA is taken up intracellularly and that active dexamethasone is released.
Studies similar to those described above are now being carried out in human liver slices.
LPS induction in human liver slices also increased TNFα production to the same extent as
was found in rat liver slices [104] (Figure 12.10). Human liver slices also produced IL-6, IL-8
and IL-1β, although the latter to a lesser extent than that observed in the liver slices of rat origin.
However, human liver slices produced less NO after LPS stimulation than those of the
rat. More experiments will be undertaken to elucidate this species difference.
Taken together these results indicate that non-parenchymal cells are still active in the slice
preparations and that intercellular communication is still intact. Furthermore, pharmacological
intervention by anti-inflammatory drugs can be successfully studied in liver slices. Together
with the results obtained in regard to drug transport, liver slices seem to be a very
promising in vitro system for studying intercellular distribution, cellular processing and effectiveness
of anti-inflammatory drugs coupled to a targeting device.
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