Biomedical Engineering Reference
In-Depth Information
compound is governed by its ability to interact with lipophilic cell membranes, and, thus, its lipophi-
licity (Figure 9.7). This has been utilized in many prodrug strategies adding lipophilic promoieties to
hydrophilic drug molecules or lead compounds. A few examples are given in the following text.
Pivampicillin, talampicillin, and bacampicillin are the pivaloyloxymethyl, the phthalidyl, and
the ethoxycarbonyloxyethyl esters, respectively, of the parent penicillin ampicillin (Figure 9.9).
These esters offer a signii cant increase in lipophilicity in comparison with the parent ampicillin by
blocking the carboxylic function and adding lipophilic groups to the molecule.
As it appears from Figure 9.10, the prodrug strategy for pivmapicillin involves a double ester in
which an initial enzymatic-mediated process is followed by a fast and spontaneous reaction. This
principle has been successfully used to improve the oral bioavailability of ampicillin from about
30%-40% to essentially complete absorption. Thus, by employing the prodrug principle, unab-
sorbed drug that may negatively interact with bacteria in the gastrointestinal tract will be signii -
cantly limited for the benei ts of patients receiving the drug.
A major problem in the use of the b-adrenergic antagonist timolol (Figure 9.11) in the treatment
of glaucoma is the high incidence of cardiovascular and respiratory side effects. This is due to
absorption of the topically applied drug into the systemic circulation, which again can be attrib-
uted to insufi cient corneal penetration of the drug. The use of more lipophilic prodrugs has been
investigated to improve the corneal penetration of timolol and it was found that O -butyryl timolol,
which is 50 times more lipophilic than timolol (Figure 9.11), was absorbed into the aqueous humor
R
S
CH
NH 2
CO
NH
CH 3
CH 3
H
N
Ampicillin
COOR
CH 2 OCOC(CH 3 ) 3
Pivampicillin
CH(CH 3 )OCOOC 2 H 5
Bacampicillin
O
O
Talampicillin
CH
FIGURE 9.9
Ampicillin, pivampicillin, talampicillin, and bacampicillin.
S
S
Enzymatic
HOOCC(CH 3 ) 3
COO
CH 2 O ( 3 ) 3
COO
CH 2 OH
Pivalic acid
Pivampicillin
Spontaneous
S
H 2 CO
Formaldehyde
COOH
Ampicillin
FIGURE 9.10
Biotransformation of pivampicillin.
 
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