|dc.description.abstract||Prodrugs are inactive precursors of an active drug designed to
be bioconverted (activated) post administration with the main
aim of improving the pharmacokinetic properties of the parent
drug. Prodrugs have been successful for a longtime.
Sulfasalazine, one of the earliest prodrugs, reaches the colon
and is metabolized by bacteria into two active metabolites:
sulfapyridine and 5-aminosalicylic acid (5-ASA). Sulfasalazine
was approved for use in the USA in 1950 and still is considered
first-line treatment in autoimmune conditions such as Crohn’s
disease and ulcerative colitis . It has been demonstrated
that the prodrug approach has reached vast success in the
past few years. It is estimated that around 10% of all marketed
drugs are prodrugs, 20% of small molecular weight drugs
approved between 2000 and 2008 were prodrugs, and
between 2008 and 2017 the share of prodrugs in the drug
market was 12% .
Various strategies are employed in the prodrug approach.
The most common of which is making a prodrug susceptible
to abundant enzymes by functionalization with a group that
can be cleaved to produce the active form of the drug. The
prodrug approach to drug optimization offers chemical stability
such as an inactive oral prodrug can be stable in the
gastrointestinal tract and only be bioconverted by CYP450 in
the liver, plasma, or GIT mucosal esterase, or other enzymes.
Examples of this include phosphate groups which are susceptible
to alkaline phosphatase, ester groups which are susceptible
to esterases, and carbamates or amidine groups which
are susceptible to amidases. Newer strategies include pegylation,
which is used to increase cellular uptake, and dimer
prodrugs, which are cleaved to two active moieties.
Also, prodrugs can be used as precursors in biological
conversion pathways, as is the case with L-dopa, a prodrug
of dopamine. L-dopa crosses the blood-brain barrier through
L-type amino acid transporter-1 and is metabolized by aromatic
amino acid decarboxylase to active dopamine in the
CNS. Targeted prodrugs have also been explored in oncology
in order to minimize side effects and improve the tolerability
of chemotherapy .
Prodrugs are also used to increase the duration of action of
medicines, acting as chemical sustained release forms.
Lisdexamfetamine dimesylate is an inactive prodrug of amphetamine used mainly in the treatment of attention deficit
hyperactivity disorder (ADHD). The prodrug is hydrolyzed by
red blood cells to L-lysine and active d-amphetamine. The
duration of action of lisdexamfetamine is 12 h  compared
to that of instant release amphetamine, which is 3-6 h.
In cardiovascular medicine, prodrugs have been successful.
Older prodrugs such as angiotensin-converting enzyme inhibitors
(ACEi) are considered cornerstones in the management
of hypertension. ACE inhibitors are dicarboxyl ester prodrugs
converted to their active -rilat form by liver esterase (such as
enalapril and enalaprilat). The exceptions for this are lisinopril
and captopril which are not prodrugs, and fosinopril, which is
a phosphonic acid prodrug hydrolyzed by liver and GIT
mucosa esterases. Newer prodrugs, such as dabigatran etexilate
and prasugrel (Table 1), are anticoagulants indicated for
the treatment and prevention of blood clotting.
Prodrugs of nucleoside analogs are used to improve pharmacokinetic
properties such as intestinal permeability and oral
absorption . For instance, valacyclovir and valganciclovir
are valine ester prodrugs of acyclovir and ganciclovir, respectively,
target intestinal oligopeptide transporter aiming to
improve the oral absorption of the parent drug.||en_US