Drug Targeting Organ-Specific Strategies

• The DC in non-target sites, including the plasma compartment (central compartment).The
drug–carrier conjugate in the non-target sites may be modelled as a single compartment, if
DC distributes rapidly over its distribution volume.That is, the plasma compartment in the
case of large macromolecular carriers which cannot cross the endothelial lining of blood
vessels, or the extracellular volume in the case of smaller compounds which do have the
opportunity to extravasate. Both administration (except for delivery to the target site) and
elimination occur in this DC central compartment. If necessary, one or two peripheral
compartments may be added to improve the accuracy of predicting the distribution of the
DC concentrations in the body.
• DC in target sites (response compartment). The drug–carrier conjugate is targeted by
some specific mechanism to the target site. The volume of this compartment depends on
the specificity of this mechanism, and can also be influenced by the disease process which
is being targeted. This value may range from a few milliliters (for a focal inflammation or
infection site) to several liters (for a widely spread disease) [40].
• D in target sites (response compartment). Ideally, the target site of the drug is located very
near to the DC target site, where the drug is released or activated. In that case, the target
sites of DC and D are identical, and any amount of drug released or activated may exert
its effect immediately. However, if the drug is released or activated at sites distant from the
target site of the drug, an additional compartment is required. This will have a detrimental
effect on the efficacy of the targeting strategy [40].
• D in non-target sites, including the plasma compartment (central compartment). After release
or activation of the drug in or near the target site, the drug will be transported to the
plasma compartment by diffusion and/or convection. Also, some drug may be released or
activated at non-target sites. The central compartment in which the drug distributes may
vary, depending on its physicochemical properties: from a minimum value equal to the
plasma compartment to high values, exceeding the physical volume due to excessive binding
of the drug to tissue components [10]. Elimination of the drug occurs from this central
compartment. If necessary, one or two peripheral compartments may be added to enable a
more accurate prediction of the drug concentrations in the body to be made. If drug D is
converted to active metabolites, additional compartments to account for the fate of these
metabolites may be required.
The central compartment may also include the sites where toxicity occurs. Alternatively,
these sites may be modelled as compartments connected to the central compartment, analogous
to the D target-site compartment. If the drug is released or activated within these toxicity
sites, and/or the drug carrier is targeted to some degree to these sites, an additional DC
compartment should be modelled, analogous to the DC target site.
Using the model shown in Figure 13.3, the main processes involved are the following.
13.3.1.1 Disposition of DC
13.3 Pharmacokinetic Models for Drug Targeting 351
This refers to the distribution and elimination of the DC, excluding transport to the target
site (and toxicity site, as shown in Figure 13.4). In general, it is desirable that the DC is not
rapidly eliminated from the circulation. This is necessary both to minimize the exposure of