Drug Targeting Organ-Specific Strategies

12 Use of Human Tissue Slices
in Drug Targeting Research
Peter Olinga, Geny M. M. Groothuis
12.1 Introduction
Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer
Copyright © 2001 Wiley-VCH Verlag GmbH
ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)
It has long been recognized that in vitro research can provide valuable information on basic
mechanisms with respect to kinetics and efficacy of drug targeting concepts. Such in vitro research
includes the use of isolated cells, cell lines and perfused organs. In this chapter the introduction
of tissue slices into drug targeting research will be discussed.A brief history of the
slice technique will first be given. Until now most research on the slice technique has been focused
on the metabolism and transport of drugs and this topic will therefore be summarized
before embarking on a discussion of the contribution of the tissue slice technique to the area
of drug targeting research.
In vitro research began with organ culture of embryonic organ rudiments [1]. The slice
technique, using slices of tumour and liver tissue, was performed as early as 1923 by Otto
Warburg [2] and in the following years by H. A. Krebs [3], who investigated the metabolism
of amino acids in liver slices of cats, dogs and rats. These liver slices were prepared manually
with limited reproducibility and viability [4].After a decline in the application of slices in liver
research in favour of the use of isolated hepatocytes as well as isolated perfused liver
preparation, the development of the Krumdieck slicer in the 1980s led to a ‘comeback’ of the
technique enabling the production of reproducible and viable liver slices [5].This technology
induced a renaissance of the slice technology.The development of these in vitro preparations
has been of paramount importance for research on human liver function. As most of the research
with tissue slices concerned the liver, this chapter will focus on the use of liver as the
target tissue and only briefly mention the use of slices from other tissues in the concluding
section of the chapter.
The most abundant cell type in the liver is the hepatocyte, other cells in the liver are the
non-parenchymal cells: Kupffer cells, the resident macrophages of the liver, endothelial cells
and stellate cells. These cells have been discussed in more detail in Chapter 4.
Since a high yield isolation procedure of rat hepatocytes was described in 1969 [6], hepatocytes
have become the model of choice for drug transport studies in the liver in vitro [7].
With this procedure, isolated hepatocytes from many species have been prepared, including
hepatocytes from rat, mouse, chicken, dog, fish, hamster, pig, cow, sheep and monkey liver
(for an extensive review see reference [8]). Before 1976, only relatively small numbers of human
hepatocytes could be isolated, due to the use of non-perfusion techniques [9]. Bojar et al.
[10] were the first to use a perfusion technique on human livers which greatly enhanced the
yield of hepatocytes. In principle the procedure that is now commonly used, is based on the
one described by Seglen [6] for rat hepatocytes. Either a biopsy wedge with intact capsula on