Drug Targeting Organ-Specific Strategies

132 5 Delivery of Drugs and Antisense Oligonunucleotides to the Proximal Tubular Cell
[24]. Uptake which has the effect of concentrating the therapeutic agent is one of the advantages
of using receptor- and/or transporter-mediated drug delivery.
The critical factors that need to be addressed include the limited range of drugs that can be
delivered by this system. The present findings suggest that the system cannot be applied to macromolecules
such as genes and proteins. For application to low-molecular-weight compounds,
the therapeutic activity of the drug needs to be regained after release from its vector in the
kidney. The pharmacological activity of AVP was affected by derivatization [40,41] and our
recent findings suggest that the kidney-targeting potential is low for certain types of anionic drugs.
It should be noted also that distribution may occur to organs other than the kidney. For example,
oxytocin derivatives also exhibited CL uptake in the small intestine. A similar phenomenon
was observed for Glc-S-C8-tryptamine where the CL uptake in small intestine and liver
also increased by derivatization [24]. These findings cannot be explained simply by the existence
of a single binding site for alkylglycoside vectors in the different organs. The presence
of multiple binding sites is supported by the finding that inhibition of the specific binding of
Glc-S-C8-tyrosine by Glc-S-C8-AVP cannot be fitted to a single site kinetic model [37]. To
clarify the renal and extra-renal transport mechanisms, kinetic analysis performed by changing
the structure of the ligand may not be sufficient and molecular biological analysis may be
helpful, for example by characterizing the target binding protein. This should reveal the
scope and limitations of this alkylglycoside strategy in clinical and pathological situations.
5.2.2 The Amino Acid Pro-drug Approach
5.2.2.1 Introduction
Most research on tubular cell-specific drug delivery has been focused on the development of
pro-drugs that should be activated by more or less kidney-selective enzymes.The relevant literature
will be reviewed briefly and discussed with regard to the benefits and limitations
compared to the alkylglycoside and macromolecular approaches of renal drug targeting.The
‘soft drug’ concept will be discussed as a potential method by which targeted drugs are inactivated
efficiently after reentering the circulation.
5.2.2.2 The Concept of the Amino Acid Pro-drug
In the design of drugs, the usefulness of renal-specific enzymes which enable the site-specific
release of the active drug, should be taken into account.The design of kidney-selective prodrugs
is based upon the relatively higher amounts of certain enzymes in the proximal tubular
cells than elsewhere in the body.
These strategies are aimed at either cytosolic enzymes, such as L-amino acid decarboxylase,
β-lyase and N-acetyl transferase, or enzymes that are expressed at the brush border of
the proximal tubule and to a lesser extent on the basolateral membrane, such as γ-glutamyl
transpeptidase (GGT).
The technology involves one or more chemical modifications of the parent compound using
chemical moieties that, with regard to size, are comparable to or even smaller than the