Biomedical Engineering Reference
In-Depth Information
O
N
OCH
2
CH
OR
CH
2
NH
C(CH
3
)
3
N
N
S
R
Log D
-- H
-0.04
Timolol
-- C O ( C H
2
)
2
CH
3
2.08
O
-Butyryl
-- COCH(C
2
H
5
)
2
3.26
O
-2-Ethylbutyryl
-- COCH
2
C(CH
3
)
3
3.09
O
-3,3-Dimethylbutyryl
-- C O c C
3
H
5
1.74
O
-Cyclopropanoyl
FIGURE 9.11
Timolol and its
O
-alkyl esters.
four to i ve times better than timolol, while yielding similar plasma timolol concentrations. In addition
to this, it has been shown that the
O
-butyryl timolol prodrug offers extended duration of action in
comparison with the parent timolol in an experimental animal model. This is most likely due to the
more lipophilic prodrug being held in the ocular tissue compartment, which may act as a depot from
which the drug is being slowly released. It should, however, be noted that although the
O
-butyryl
timolol ester and other alkyl esters indeed increase corneal absorption they at the same time suffer
from chemical instability in aqueous solution. However, the chemical stability could be substantially
improved by introducing sterically hindered esters such as the 2-ethylbutyryl, 3,3-dimethylbutyryl,
and cyclopropanoyl derivatives.
9.4.1.3 Improved Transporter-Mediated Permeability
Various active transport mechanisms for amino acids, small peptides, monocarboxylic acids,
monosaccharides, and nucleosides exist in the human body and it is generally recognized that such
mechanisms play a major role in the absorption of many drug molecules. This has been used in prodrug
design attempting to provide chemical bioreversible modii cations mimicking natural substrates for
various active transporters with the aim of improving intestinal absorption of various drugs.
The oral absorption of the antiviral compound gangciclovir (Figure 9.12) is less than 10%.
Valgangciclovir, the corresponding l-valine ester of the compound, however, shows a marked
increase in oral bioavailability of about 60%. This is mainly ascribed to the transport of the prodrug
across the gastrointestinal epithelium, which is mediated by a small peptide active transport mecha-
nism for which gangciclovir is not a substrate.
Another example of facilitating active absorption processes by the use of prodrugs is levodopa.
Levodopa (or l-dopa) is a prodrug of the neurotransmitter dopamine and utilizes the l-aromatic
amino acid transporter for permeation of the intestine and the blood-brain barrier. The active com-
pound dopamine is regenerated by decarboxylation mediated by dopamine decarboxylase enzymes
(Figure 9.13).
9.4.1.4 Increased Stability in the Gastrointestinal Tract
The poor absorption of carbenicillin (Figure 9.14) after oral administration can to a large extent be
attributed to fast acid-catalyzed degradation in the gastrointestinal tract. More acid resistant pro-
drugs such as carindacillin and carfecillin (Figure 9.14) have been shown to signii cantly increase
the bioavailability of cabenicillin.
