Biomedical Engineering Reference
In-Depth Information
specii cally inhibits the enzyme gastric H
+
-K
+
-ATPase that is responsible for the gastric acid
production and is located in the secretory membranes of parietal cells. Omeprazole itself does not
inhibit this enzyme but is biotransformed within the acid compartments of the parietal cells into the
active inhibitor cyclic sulfonamide, which reacts with cysteine thiol groups of the enzyme thereby
inactivating it (Figure 9.17).
Since omeprazole is only converted to the active molecule at acidic conditions, bioactivation
almost exclusively takes place at the low pH at the parietal cells where high concentrations of the
active species are generated.
Another example of site-specii c delivery using the prodrug approach is olsalazine, which is
being used in the treatment of ulcerative colitis. The active drug 5-aminosalicylic acid (mesalazine)
is delivered from olsalazine to the colon due to specii c bioactivation mediated by azo-reductases
produced by anaerobic colonic bacteria. Olsalazine acts as a so-called twin prodrug in that it is
cleaved to yield two molecules of the parent drug (Figure 9.18).
Drug targeting to the brain has been investigated using uptake transporters in the blood-brain
barrier as targets for prodrugs. For example, glucose and mannose derivatives of levodopa and
dopamine have shown increased
in vivo
activity in animal models compared to parent compounds.
This has been attributed to enhanced drug transport into the brain by prodrugs utilizing the glucose
transporter in the blood-brain barrier. Other brain uptake systems such as the large amino acid
transporter have been the target for prodrugs.
Finally, it should be mentioned that the use of monoclonal antibodies as potential promoieties for
anticancer agents may be of interest since such antibodies offer high specii city toward its target.
The principle of using antibodies as promoieties will theoretically offer selective drug attachment
to cancer cell antigens followed by release of the active drug leading to a higher drug accumulation
at the site of action and thereby increased therapeutic effectiveness.
OCH
3
OCH
3
OCH
3
H
3
C
CH
3
H
3
C
H
3
C
CH
3
CH
3
H
+
Enzyme
SH
N
N
N
N
SO
S
S
S
Enzyme
N
NH
N
N
NH
H
3
CO
OCH
3
OCH
3
FIGURE 9.17
Omeprazole—bioconversion and mechanism of action.
HOOC
COOH
H
2
N
COOH
2
HO
N
N
OH
OH
Olsalazine
Mesalazine
FIGURE 9.18
Bioactivation olsalazine—a twin prodrug.
