Drug Targeting Organ-Specific Strategies

5.2 Renal Delivery Using Pro-Drugs 133
parent drug. This type of pro-drug may be degraded intracellularly into the active drug, resulting
in its release and subsequent secretion into the tubular lumen or via the interstitium
back into the circulation.
Alternatively, the pro-drug may be a substrate for brush-border enzymes of the proximal
tubular cell, resulting in release of the active drug in the tubular lumen and subsequent reabsorption
at distal sites or elimination in the urine.
5.2.2.3 Renal Specificity of Amino Acid Pro-drugs and their Effects
Several drugs have been coupled to gamma-glutamyl transferase, γ-glutamyl. The γ-glutamyl
pro-drug of l-dopa (gludopa) showed a higher renal specificity [42–44] than the pro-drug of
dopamine [45]. Gludopa induced renal-specific effects such as increases in renal blood flow
and salt excretion while systemic blood pressure remained unaffected [42,43].
Another example is the pro-drug γ-glutamyl-sulphamethoxazole. This pro-drug did not
show renal selectivity, either because of its rapid removal from the kidney, or due to cleavage
in non-target tissues containing a low concentration of the enzyme. On the other hand the Nacetyl-γ-glutamyl
derivative showed pronounced renal specificity [46,47]. In this respect, prodrug
accumulation in the kidney was due to carrier-mediated transport at the basolateral
membrane site, which is sensitive to buthionine sulfoximine and probenecid. Other N-acetylγ-glutamyl
pro-drugs have been developed and tested on the basis of the same principle. Of
the derivatives tested, N-chloroacetyl-γ-glutamyl-sulfamethoxazole appeared to have the
highest renal selectivity [46]. N-acetyl-γ-glutamyl-aminowarfarin was not a successful prodrug
since it was not rapidly secreted via the tubule and therefore did not reach the enzyme
site [48]. In fact, this pro-drug was selectively excreted in the bile.
The N-acetyl-γ-glutamyl pro-drug of the hydralazine-like vasodilator CGP 18137 showed
a higher renal-selective activity than the parent compound, CGP 18137. In contrast to the
parent drug, the pro-drug caused a decrease in renal resistance without any effect on blood
pressure [49].
Because of the high phosphatase activity in the kidney, dopamine-phosphate ester prodrugs
have been synthesized, e.g. SIM 2055 (N-methyl-dopamine-4-O-phosphate) [50]. Although
the mechanism of renal selectivity of this compound is not yet understood in detail, it
is thought to be due to the high renal blood flow and the high renal phosphatase activity together
with the high affinity of the kidney for the released drug.
Cysteine-S-conjugates have also been proposed as kidney-selective pro-drugs. Renal metabolism
of S-6-(purinyl)-L-cysteine resulted in the formation of 6-mercaptopurine by the action
of β-lyase [51]. However, besides formation of the intended parent compound, other Sconjugates
may be formed by various radical reactions, which may induce renal toxicity.
5.2.2.4 Benefits and Limitations of the Amino Acid Pro-drug
A potential benefit of the pro-drug approach is that the compounds can, in principle, be designed
for oral administration. Furthermore, immunogenicity which results from using protein
conjugates as drug carriers, will not be a problem. However, in contrast to the LMWP ap-