4.1 Definitions
123
1989 (Bundgaard 1989), has also been classified separately as a third main
group (Jubeh et al. 2020) but not always. An example of a double prodrug
is that of pivampicillin, a double ester, lipid-soluble prodrug of the antibiotic ampicillin. Esterase-mediated hydrolysis of the terminal ester group in
this prodrug then exposes a chemically unstable hydroxymethyl ester goup
which fragments to ampicillin plus formaldehyde. This prodrug type can be
extended to a triple prodrug design, in which three steps would be involved
in the transformation to the active drug.
(ii) a cascade prodrug which is related to a double prodrug, but is defined separately in the IUPAC glossary of terms as being one “for which the cleavage of
the carrier group becomes effective only after unmasking an activating group.”
(Wermuth et al. 1998).
Cascade prodrugs are normally either bipartite in design with the drug directly
attached to a procarrier or in the tripartite category with a drug-linkerprocarrier design.
(iii) a mutual prodrug which “is the association in a unique molecule of two,
usually synergistic, drugs attached to each other, one drug being the carrier for
the other and vice versa” (Wermuth et al. 1998). With a mutual prodrug, or also
referred to as a co-drug (Das et al. 2010), the two synergistic drugs are chemically linked, with a view to improving the delivery properties of one or both
drugs. The drugs treat the same disease but may mediate treatment via different
mechanisms of action after selective cleavage in vivo. An example here is the
orally administered drug, Sultamicillin, in which ampicillin is joined to the
irreversible β-lactamase inhibitor sulfabactam via a methylene linked diester
derived from the carboxylic acid groups on each. After absorption, esterasemediated ester hydrolysis occurs followed by spontaneous formaldehyde loss
resulting in self-immolation of the linker (Rautio et al. 2018) and release of
the broad-spectrum antibiotic ampicillin plus sulbactam (Singh 2004).
(iv) a macromolecular prodrug which is one in which the carriers used involve
macromolecules including polysaccharides, dextrans, cyclodextrins, peptides,
proteins and other polymers (Parajuli et al. 2015).
(v) a site-specific prodrug in which the prodrug is directed to a specific site
for release. This can be particularly important to avoid unwanted off-target
actions and to enhance efficacy. With a site-specific prodrug the carrier can
play a salient targeting role (Parajuli et al. 2015).
4.1.2 Bioprecursor Prodrugs
According to Wermuth et al. (1998) a “bioprecursor prodrug is a prodrug that does
not imply the linkage to a carrier group, but results from a molecular modification
of the active principle itself. This modification generates a new compound, able to
be transformed metabolically or chemically, to the resulting compound being the
active principle.” Thus with these prodrugs there is no separate carrier group and
123
1989 (Bundgaard 1989), has also been classified separately as a third main
group (Jubeh et al. 2020) but not always. An example of a double prodrug
is that of pivampicillin, a double ester, lipid-soluble prodrug of the antibiotic ampicillin. Esterase-mediated hydrolysis of the terminal ester group in
this prodrug then exposes a chemically unstable hydroxymethyl ester goup
which fragments to ampicillin plus formaldehyde. This prodrug type can be
extended to a triple prodrug design, in which three steps would be involved
in the transformation to the active drug.
(ii) a cascade prodrug which is related to a double prodrug, but is defined separately in the IUPAC glossary of terms as being one “for which the cleavage of
the carrier group becomes effective only after unmasking an activating group.”
(Wermuth et al. 1998).
Cascade prodrugs are normally either bipartite in design with the drug directly
attached to a procarrier or in the tripartite category with a drug-linkerprocarrier design.
(iii) a mutual prodrug which “is the association in a unique molecule of two,
usually synergistic, drugs attached to each other, one drug being the carrier for
the other and vice versa” (Wermuth et al. 1998). With a mutual prodrug, or also
referred to as a co-drug (Das et al. 2010), the two synergistic drugs are chemically linked, with a view to improving the delivery properties of one or both
drugs. The drugs treat the same disease but may mediate treatment via different
mechanisms of action after selective cleavage in vivo. An example here is the
orally administered drug, Sultamicillin, in which ampicillin is joined to the
irreversible β-lactamase inhibitor sulfabactam via a methylene linked diester
derived from the carboxylic acid groups on each. After absorption, esterasemediated ester hydrolysis occurs followed by spontaneous formaldehyde loss
resulting in self-immolation of the linker (Rautio et al. 2018) and release of
the broad-spectrum antibiotic ampicillin plus sulbactam (Singh 2004).
(iv) a macromolecular prodrug which is one in which the carriers used involve
macromolecules including polysaccharides, dextrans, cyclodextrins, peptides,
proteins and other polymers (Parajuli et al. 2015).
(v) a site-specific prodrug in which the prodrug is directed to a specific site
for release. This can be particularly important to avoid unwanted off-target
actions and to enhance efficacy. With a site-specific prodrug the carrier can
play a salient targeting role (Parajuli et al. 2015).
4.1.2 Bioprecursor Prodrugs
According to Wermuth et al. (1998) a “bioprecursor prodrug is a prodrug that does
not imply the linkage to a carrier group, but results from a molecular modification
of the active principle itself. This modification generates a new compound, able to
be transformed metabolically or chemically, to the resulting compound being the
active principle.” Thus with these prodrugs there is no separate carrier group and