PRODRUG

LEC 5
ENAS SAMI ALI
 Chemical Delivery Systems
Prodrug may be used to target a drug to its site of action. Site specific
chemical delivery systems take advantage of higher levels of activity
in a metabolic or chemical pathway at the target site.
A prodrug form of the active drug is designed to serve as a substrate in
that specific pathway, thus yielding a high concentration of active drug
at the target site.
Site-specific chemical delivery requires that the prodrug reaches the
target site and that the enzymatic or chemical process exists at the
target site for conversion of the prodrug to the active drug.
Many factors are involved in the relative success of site-
specific drug delivery, including;
1-Extent of target organ perfusion.
Since high metabolic activity occurs in highly perfused tissues such as
liver and kidney, delivery to these organs has a natural advantage
2-Rate of conversion of prodrug to active drug in both target and non-
target sites.
On arrival at the target site, the prodrug should be selectively converted
to drug relative to its rate of conversion at non target sites.
3-Input/output rates of prodrug and drug from the target sites.
It is highly desirable to have the active drug once formed ,migrate from
the target site at slow rate
Aim of site specific chemical delivery systems
1- increased therapeutic effectiveness 2- decrease side effects.
As the fate of drugs in the human body has become more clearly
understood, research activity to improve the delivery of active drug to the
target site has increased.
The basic goal of these efforts is
1-to protect the drug from the nonspecific biological environment
2-to protect the nonspecific bio-environment from the drug to achieve
some site-specific drug delivery.
3-Site-specific drug delivery has been evaluated extensively for drugs
with narrow therapeutic windows, such as many of the anticancer drugs.
Yet there are several excellent examples of site-specific chemical
delivery systems in use in modem drug therapy.
The target sites include
Cancer cells
GI tract
Kidney
Urinary tract
Bacterial cells
Viral material
Blood brain barrier.
 Urinary Tract Targeting
The prodrug methenamine, described previously, can be considered a
site-specific chemical delivery system for the urinary tract antiseptic
agent formaldehyde. The low pH of the urine promotes the hydrolysis
of methenamine to formaldehyde, the active antibacterial agent. The
rate of hydrolysis increases with increased acidity (decreased pH), and
this can be promoted by administration of urinary pH-lowering agents
or by diet. The pH of the plasma is buffered to about 7.4, and the rate of
hydrolysis is low, preventing systemic toxicity from formaldehyde. As
mentioned previously, this compound is administered in enteric coated
tablets that prevent dissolution and, therefore, premature hydrolysis in
the highly acidic environment of the stomach.
 Cancer Cells Targeting
A number of prodrugs for cancer chemotherapy have been designed
for selective delivery of active drug to tumor tissue, based on higher
levels of activating enzyme in the tumor cell than in normal tissue.
Many enzymatic systems show higher activity in tumor cells than in
normal tissue because of the higher growth rates associated with
tumor tissue. Peptidases and proteolytic enzymes are among those
systems showing higher activity in and near tumor cells. Thus, one
means of attempting to produce higher rates of drug incorporation
into tumors than in surrounding normal tissue involves deriving a
drug molecule with an amino acid or peptide fragment
Capecitabine is an example of a prodrug chemical delivery system that
requires a series of enzymatic steps for conversion to the active
antitumor drug species, 5-Fluorouracil. Tumors located in tissues with
high levels of the required enzymes should respond best to treatment
with capecitabine. Esterase activity occurs primarily in the liver,
allowing the intact ester capecitabine to be the absorbed species
following oral administration. The ester hydrolysis product itself shows
some specific toxicity toward GI tract tissue, which prevents this
molecule from serving as an effective prodrug delivery form of 5-
fluorouracil. The other two enzymes involved in the formation of 5-
fluorouracil occur in high concentrations in target tissues such as cervix,
breast, kidney, and colon
The intracellular media of cancer cells can be differentiated from that
inside healthy cells resulting in the advantage of site-specific chemical
activation of anticancer prodrugs. Additionally, it is known that certain
glycosylases, for instance βglucuronidase, and peptidases, as plasmin or
prostate-specific antigen, are expressed in the extra cellular space of
tumors in comparatively high concentrations. By attachment of a
promoiety to a cytotoxic compound that can be cleaved by the action of
these enzymes, a site-specific activation of the prodrug inside the tumor
tissue can be observed leading to lowered toxicity in healthy tissue.
Further development of this approach led to the antibody directed
enzyme prodrug therapy (ADEPT), where a detoxified prodrug of a
cytotoxic agent is applied in combination with an antibody enzyme
conjugate.
By directing the conjugate to tumor specific antigens, the enzymatically
triggered activation of the prodrug takes place inside the tumor tissue,
thereby enabling a somewhat specific cytotoxic therapy
 Blood Brain Barrier Targeting
The amino acid drug L-dopa can be considered a site specific chemical
delivery system that delivers the drug dopamine to the brain. The brain
has an active transport system that operates to incorporate L-amino
acids into the central nervous system (CNS), and L-dopa is transported
into the brain in this manner. Once across the blood brain barrier, L-
dopa undergoes decarboxylation to yield the active metabolite,
dopamine. Direct systemic administration of dopamine does not
produce significant levels of the drug in the brain because of its high
polarity and poor membrane permeability as well as its facile metabolic
degradation by oxidative deamination. Dopamine formed on the inside
of the blood brain barrier is held there.
however, because of the poor membrane permeability of this drug.
Although some specificity for brain tissue is achieved by this delivery
method, peripheral side effects of L-dopa (Levodopa) are the direct
result of decarboxylation to dopamine in other organ systems. In this
case, the enzyme activating system is not localized at the target site, and
its presence in other tissues and organs leads to undesirable side effects.
 Colon Targeting
The delivery of drugs to the colon and lower GI tract has taken
advantage of the unique enzymatic processes found in colon bacteria.
The glucosidase activity of these bacteria allows hydrolysis of
glucoside derivatives of drugs in the colon and provides higher
concentrations of active drug. A number of steroid drugs demonstrate
increased effectiveness in the lower GI tract following administration
as their glucoside derivatives. The polar glucoside derivatives of the
steroids are not well absorbed into the bloodstream from the GI tract
and remain available to serve as substrates for the bacteria that are
found primarily in the human colon.