Drug Targeting Organ-Specific Strategies

13.3.1.3 Release or Activation of D at the Target Site
The release of the drug from the drug–carrier conjugate or the formation of the active moiety
from the pro-drug, is also reported to be of major concern in many research papers on
drug targeting (see other chapters in this book). Although this process cannot be measured
in vivo in most cases, valuable information can be obtained from in vitro measurements, for
example, using cultured cell lines. The mechanism of release or activation may contribute to
the selectivity of the target site, for example, in case of the formation of the phosphorylated
active forms of nucleoside analogues by viral enzymes. In the case of release or activation by
enzymatic processes, the rate of release or activation may be limited by saturation of the enzyme
capacity.
In general, rapid release contributes to the efficiency of drug targeting, although in many
cases the rate of release may not be critical as a result of rate limitation in the delivery of the
DC to the target site. With respect to the selectivity of the target site for the release or activation
in comparison to non-target sites, it can be stated that the more selective the delivery
of the DC to the target site, the less important is the selectivity of the release or activation at
the target site.
13.3.1.4 Removal of D from the Target Site
13.3 Pharmacokinetic Models for Drug Targeting 353
Little attention has been paid to this aspect in most research papers on drug targeting, despite
several reports on the importance of removal of the released drug from the target site
[6,12,42]. Most likely, this lack of attention is related to at least three factors: removal of drug
from the target site (1) cannot be manipulated by the design of the drug targeting system, (2)
is difficult to measure, and (3) may be the bottleneck of the efficiency of drug targeting
strategies.
A striking example of the importance of the secondary removal of a drug from the target
site are the multi-drug-resistance (MDR) processes of tumour cells. For instance antineoplastic
drugs can be extruded efficiently by P-glycoprotein [43]. Although this example is
only relevant for a limited category of drugs, it clearly demonstrates that the delivery of a
drug into a cell does not guarantee an optimal retention time in the cell nor an optimal drug
effect. Levy [42] assumed that in many cases drug elimination from the target site will be
much more rapid that drug elimination from the body, as exemplified for intracerebroventricular
injections of barbiturates.
Removal of active drug from the target site can occur by two different routes: direct removal
by a local elimination process (typically a metabolic process, causing inactivation of
the drug), or removal by the blood flow following diffusion out of the target cell. In both cases
removal reduces the efficiency of drug targeting by lowering the concentration of the active
drug at the target site. However, in case of local removal, the active drug is not transported
to non-target tissues, and does not contribute to toxicity. In contrast, removal by the
bloodstream causes an increase of concentration in the non-target tissue, thus lowering the
targeting efficiency further. It may be noted that a high blood flow to the target tissue favours
the delivery of the DC to the target site, but also increases the rate of removal of the active
drug. Ideally, the active drug should be eliminated slowly from the target site, so that effec-