Drug Targeting Organ-Specific Strategies

336 13 Pharmacokinetic/Pharmacodynamic Modelling in Drug Targeting
• Distribution of the drug throughout the body, characterized by the volume of distribution
(V) which is defined as the amount of drug in the body divided by the drug concentration
in plasma;
• Metabolism, the biotransformation of the drug into metabolites, which may be inert, active,
or toxic;
• Excretion of the intact drug, and its metabolites, into urine and faeces.
The term ‘elimination’ is used as a common term for the disappearance of the drug from
the body by either metabolism or excretion. The term ‘clearance’ (CL) is used as a measure
of the collective capacity of the eliminating organs to remove a certain drug, and is defined
as the rate of drug elimination (amount/time) divided by the drug concentration in plasma,
and indicates the volume of plasma that is cleared from the drug per unit of time (dimension
volume/time). The elimination rate constant (k) is defined as the rate of drug elimination
(amount/time) by the amount of drug in the body, and is equal to the clearance divided by
volume of distribution (CL/V). The (elimination) half-life (t 1/2) is the time taken for the plasma
concentration, as well as for the amount of drug in the body, to fall by 50%, and is approximately
equal to 0.7/k [10].
In the field of drug targeting, the LADME processes refer to both the drug–carrier conjugate
and the active drug. Liberation would refer to the release of the drug from a drug–carrier
conjugate or the conversion of a pro-drug to the active moiety.
13.2.1.2 Transport Mechanisms
The transport mechanisms that operate in distribution and elimination processes of drugs,
drug–carrier conjugates and pro-drugs include convective transport (for example, by blood
flow), passive diffusion, facilitated diffusion and active transport by carrier proteins, and, in
the case of macromolecules, endocytosis. The kinetics of the particular transport processes
depend on the mechanism involved. For example, convective transport is governed by fluid
flow and passive diffusion is governed by the concentration gradient, whereas facilitated diffusion,
active transport and endocytosis obey saturable Michaelis–Menten kinetics.
13.2.1.3 Perfusion and Permeability
Both distribution of the drug within the body and elimination from the body require two sequential
steps: the transport of the drug by blood flow to the organ or tissue (perfusion), and
transport from the capillary to the tissue, and then to receptors on or in the cells of the tissue.
The latter processes are governed by the permeability of the barriers between the capillary
lumen and the receptor site, and may imply passive or carrier-mediated membrane passage.
If there are hardly any barriers for the transport to the tissue, that is, if permeability is high,
the supply of drug by the blood flow, that is, the perfusion of the organ or tissue may become
the rate-limiting step of transport. In this case a large fraction of the drug present in blood is
transported to the tissue, so the extraction ratio is high. On the other hand, if the perfusion is
high, and the barriers for the transport within the tissue are considerable, permeability, may