Drug Targeting Organ-Specific Strategies

5.1 Introduction 123
convoluted tubule, proximal straight tubule, Henle’s loop, the distal tubule and the collecting
duct. In the tubule, a monolayer of epithelial cells separates the tubular lumen from the
blood. A close network of arterial and venous capillaries provides close contact between the
blood circulation and the tubular cells.
The blood first reaches the glomerulus, the filter unit of the nephron. The glomerular filtrate,
i.e. blood deprived of macromolecules and blood cells, passes through the tubular lumen.
The blood which is not filtered, flows through the efferent arteriole into the network of
capillaries around the tubules supplying the proximal and distal tubules with blood.
5.1.2 Proximal Tubular Cells and their Functions
The proximal tubular cell plays a major role in the elimination of both inorganic and organic
substrates. The cells have two distinct membrane domains. The basolateral membrane is in
contact with the blood, and the apical brush-border membrane lines the tubular lumen.
Methods of traversing the basolateral membrane include uptake systems for organic
cations and anions via facilitated diffusion and/or active transport [1]. Organic anions and
cations cross the basolateral membrane via ATP-driven or secondary active processes (H + -
antiport) [2]. Basolateral uptake processes include the gamma-glutamyl transport system [3]
and those for glycoproteins [4]. Certain proteins (insulin, epidermal growth factor (EGF))
are transcytosed across the tubular cells from the blood to the tubular lumen via receptormediated
uptake [5].
In healthy individuals, useful endogenous compounds that are freely filtered by the
glomerulus, only appear in the urine in small quantities. These compounds are ‘rescued’ by
tubular reabsorption. These ‘rescue mechanisms’ consist of a variety of, mostly, carrier-mediated
processes at the luminal site of the tubular cell. Substances transported by reabsorptive
systems include sugars [6], amino acids [7], dipeptides [8], urate [9], folate [10], nucleosides
[11] and proteins [12].
Apart from the elimination function, the kidney disposes of many endogenous and exogenous
substances through metabolic conversion. Many compounds are highly concentrated in
the proximal tubular lumen before being eliminated in the urine [13]. Therefore the driving
force for metabolic conversion can be high. For instance metabolic clearance of indomethacin
occurs predominantly by renal glucuronidation due to efficient enterohepatic
recycling/deconjugation processes followed by carrier-mediated accumulation in the tubular
cells [14].
For exogenous compounds such as drugs, various enzymes involved in both phase I and
phase II metabolic routes are present, e.g. various isoforms of cytochrome p450, cytochrome
b5, glucuronyl transferase and sulfotransferase [15].
In addition, renal tubular cells contain various proteases for the degradation of proteins
and oligopeptides. These enzymes are located predominantly in the lysosomes and microsomes
of these cells, but some have been reported on the brush-border membranes [16].
Degradative enzymes include various endopeptidases, exopeptidases and esterases [17].
In principle, the above-mentioned transport and metabolic functions of the tubule can be
used for renal delivery and (re-)activation of (pro-)drugs and macromolecular drug targeting
preparations.