Drug Targeting Organ-Specific Strategies

5.2.1.4 Specific Binding of Alkylglycoside-derivatized AVP in Kidney
Plasma Membranes
Possible explanations for a blood flow-limited uptake in kidney include the existence of specific
uptake mechanisms, such as receptor-mediated endocytosis and carrier-mediated transport.
Since the former mechanism is initiated by binding of the ligand to the cell-surface receptor,
the specific binding of alkylglycoside compounds to isolated tubular plasma membranes
was examined [23,24].
Scatchard analysis revealed specific binding of Glc-, Man- and 2dGlc-O-C8-AVP exhibiting
kidney-specific distribution in vivo (Figure 5.3b), with a dissociation constant (Kd) of
10–60 nM.This did not occur with Gal- and Man(α)-O-C8-AVP. Saturation of the CL uptake of
Glc-O-C8-AVP in the kidney in vivo occurred at a similar concentration (40–80 nM) of unbound
ligand in the renal capillary space [23]. These results suggest that specific binding
site(s) are involved in the renal distribution of alkylglycoside conjugates of AVP.
5.2.1.5 Structure–Kinetic Relationship Studies
5.2 Renal Delivery Using Pro-Drugs 129
To develop alkylglycoside moieties as drug delivery vectors, a systematic analysis was performed
to identify the structural requirements for both vectors and drugs. This allowed us to
understand the spectrum and limitations of compounds that can be delivered by this system.
A binding study using isolated tubular membranes enabled the investigation of such struc-
Figure 5.5. Inhibition of specific binding of Glc-O-C8-AVP to rat kidney membrane fraction. Adapted
from reference [24].