Biomedical Engineering Reference
In-Depth Information
This is in agreement with Fick's i rst law of diffusion that describes the rate of diffusion across
a (bio)membrane:
d/d
Qt P A CC
=´´-
app
(
)
o
where
d
Q
/d
t
is the mass l ux across the membrane
A
is the membrane surface area
C
−
C
o
determines the initial concentration gradient between the apical and basolateral side of
the epithelium
P
app
is the permeability coefi cient
From this relationship, it follows that drug transport across the epithelium is governed by both aque-
ous solubility (generating a high initial concentration gradient) and permeability characteristics of
the compound.
Thus, optimization of the l ux and thereby the absorption potential is a balance between high
aqueous solubility and adequate permeability characteristics. This has been successfully obtained
by using the prodrug approach.
9.4.1.1 Improved Aqueous Solubility
For compounds suffering from dissolution rate or solubility limited absorption due to low aqueous
solubility and/or high therapeutic dose introduction of a hydrophilic moiety may prove benei cial for
the oral bioavailability. The most appealing type of prodrugs to overcome solubility problems are
the phosphate esters because they are generally chemically stable and at the same time enzymati-
cally labile and, furthermore, because the solubility increase obtained by phosphate esters can be
of several orders of magnitude.
The protease inhibitor amprenavir suffers from a combination of low aqueous solubility
(0.04 mg/mL) and high dose requirements (1200 mg BID corresponding to eight capsules of the
marketed product). Thus, Vertex Pharmaceuticals together with GlaxoSmithKline developed the
phosphate ester prodrug fosamprenavir (Figure 9.8) with the aim of increasing the oral bioavail-
ability of the parent drug. Fosamprenavir is rapidly and extensively hydrolyzed by alkaline phos-
phatases at the brush border of the gastrointestinal tract during or after absorption to yield the
parent active drug, amprenavir. Only minimal amounts of intact fosamprenavir reach the systemic
circulation. The development of fosamprenavir has reduced the “pill burden” for HIV patients
considerably and the prodrug can be administered without any food or water restrictions.
O
O
O
O
S
O
N
NH
2
HO
O
CH
3
P
HO
O
CH
3
FIGURE 9.8
Fosamprenavir.
9.4.1.2 Improved Biomembrane Permeability (Passive Diffusion)
Due to the large surface area of the gastrointestinal epithelium, transcellular (passive) diffusion is a
very important absorption principle for drug molecules. Thus, the ability of a compound to perme-
ate this epithelium is of vital importance for the absorption of the drug. Transcellular diffusion of a
