Drug Targeting Organ-Specific Strategies

138 5 Delivery of Drugs and Antisense Oligonunucleotides to the Proximal Tubular Cell
rectly conjugated to lysozyme. The synthesis of the conjugate with an ester spacer (naproxen–L-lactic
acid–lysozyme) is cumbersome, but fortunately the catabolite of the conjugate
with the direct peptide linkage (naproxen–lysine) appeared to have an inhibitory effect on
prostaglandin synthesis in vitro which was equivalent to that of the parent drug [66].
The coupling of 2 moles of naproxen to 1 mole of lysozyme did not affect the renal uptake
of lysozyme in the rat: like native lysozyme, the conjugate rapidly accumulated in the kidney
[75]. Focusing on the drug moiety of the conjugate, it was shown that conjugation of naproxen
to lysozyme distinctly altered the kinetics of the drug. Conjugation to lysozyme resulted in
a 70-fold increase in naproxen concentrations in the kidney (Figure 5.9a) [76].
a) b)
Figure 5.9. The concentration–time course of (a) naproxen and (b) captopril in the kidney after
intravenous injection of the parent drug or the drug–lysozyme (LZM) conjugate. Values are given as
means + SEM.
5.3.2.3 Renal Delivery of Captopril–Lysozyme
Angiotensin-converting enzyme (ACE) inhibitors such as captopril exert a long-term renoprotective
effect. Among other effects, they lower systemic blood pressure and renal plasma
flow and effectively reduce urinary protein excretion. Renal delivery of ACE-inhibitors may
increase this efficacy and reduce extra-renal side-effects. Renal targeting of an ACE-inhibitor
can also be useful in clarifying the contribution of local ACE inhibition to these renoprotective
effects.
A spacer was used to link captopril via a disulfide bond to the LMWP lysozyme. Conjugation
of captopril to lysozyme resulted in a 6-fold increase in captopril accumulation in the rat
kidney (Figure 5.9b) [77]. This modest enrichment, as compared to that achieved with
naproxen–lysozyme, was due to fact that, in contrast to naproxen, free captopril is cleared
very efficiently by the kidney itself. Thus, delivery via lysozyme reabsorption only leads to a
limited improvement of renal accumulation of captopril.