Biomedical Engineering Reference
In-Depth Information
9.4 DESIGN OF PRODRUGS—APPLICATION OF THE PRODRUG PRINCIPLE
The prodrug principle offers an opportunity for optimization of drug therapy for a variety of rea-
sons. The intention of this section is to illustrate important features of the principle by providing
selected examples of achievements by prodrug design and development.
9.4.1 D
ESIGN
OF
P
RODRUGS
WITH
I
MPROVED
B
IOAVAILABILITY
The oral bioavailability (
F
) of a compound is determined by a number of parameters such as
aqueous solubility (determines the amount of drug available at the site of absorption), perme-
ability (the ability of the molecule to permeate biological membranes), and stability in the gas-
trointestinal tract.
The relationship between lipophilicity—as measured by the distribution coefi cient (
D
) between
n
-octanol and aqueous buffer at physiological pH—and the biomembrane permeability character-
istics—as measured by the permeability coefi cient (
P
app
) across, e.g., Caco-2 cell monolayers, i.e.,
the absorption (
A
) and the oral bioavailability (
F
), respectively, is shown in Figure 9.7.
It appears that the biomembrane permeability (
P
app
) increases with increasing lipophilicity until
a certain point where the permeability is no longer controlled by the rate at which a given molecule
permeates the cell layer and from where no further signii cant improvement can be induced.
However, the mass transport that can be obtained (i.e., the l ux) and thereby the oral absorption
(
A
) and the bioavailability (
F
) tend to level off (illustrated by the shaded area in Figure 9.7) as the
increase in lipophilicity continues. This is due to the fact that an increase in lipophilicity often dic-
tates a signii cant decrease in aqueous solubility and thereby limiting the amount of drug available
for absorption (i.e., limiting the concentration gradient that can be obtained) and, consequently,
decreasing oral absorption and bioavailability. In addition to this, increased lipophilicity, in general,
promotes the afi nity to proteins such as enzymes and, thus, decreases the metabolic stability of the
compounds and thereby increases systemic clearance leading to decreased oral bioavailability.
Thus, increasing the lipophilicity of drug compounds is advantageous in terms of oral bioavail-
ability as long as it is not at the “expense” of aqueous solubility or other important parameters for
drug absorption.
Permeability
Solubility
Flux
Absorption
Efect
Interaction with proteins
Metabolism
Clearance
Flux/absorption
bioavailability
Log D
FIGURE 9.7
Relationship between lipophilicity (
D
) and (1) biomembrane permeability (
P
app
), (2) absorption
(
A
), and (3) oral bioavailability (
F
).
