Drug Targeting Organ-Specific Strategies

5 Delivery of Drugs and Antisense
Oligonucleotides to the Proximal Tubular
Cell of the Kidney Using Macromolecular
and Pro-drug Approaches
Marijke Haas, Yukio Kato, R. Folgert G. Haverdings, Frits Moolenaar, Kokichi Suzuki,
Dick de Zeeuw, Yuichi Sugiyama, Dirk K.F. Meijer
5.1 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)
The need for specific delivery of drugs to their site(s) of action is evident in the case of extremely
toxic agents that have to be administered in high doses such as anti-tumour drugs.
But what would be the rational for specific drug targeting to the kidney? Clearly, the kidney
is one of the organs with the highest exposure to drugs circulating in the body. Around 25%
of the cardiac output flows through the two kidneys. In addition, many compounds are concentrated
in the proximal tubule by active transport processes while often high luminal concentrations
of drugs are reached due to water reabsorption. So, at first glance, one may argue
that little extra would be gained by renal selective targeting. However, we believe that there
can be several good reasons for renal-specific drug delivery. First, although many drugs used
in the treatment of renal diseases do reach the kidney in sufficient quantities, they may cause
undesirable extra-renal effects. Second, the intra-renal transport of a drug may not be optimal
in relation to the target cell within the organ. Third, some drugs are largely inactivated
before they reach the site of action in the kidneys. Finally, pathological conditions such as abnormalities
in glomerular filtration, tubular secretion, or the occurrence of proteinuria can
affect the normal renal distribution of a drug. Renal-specific drug targeting therefore can be
an attractive option to overcome such problems and to improve the therapeutic index of a
drug. Furthermore, cell-specific drug targeting within the kidney may provide an interesting
tool in understanding the mechanisms of drug action and to manipulate renal physiology.
5.1.1 Kidneys and their Functions
The major function of kidneys is to filter the redundant nutrients and metabolites out of the
blood, including those that come from the natural breakdown of tissues as well as those that
we ingest with food intake. In this way, the kidneys maintain the homeostatic balance with respect
to water and electrolytes as well as nutrients and metabolites. In addition, the actions of
the kidneys also regulate blood pressure and erythropoiesis.
To do this, the kidney is equipped with nephrons, the basic units of the kidney.The nephron
consists of a glomerulus and a tubule (Figure 5.1).The tubule is subdivided into the proximal