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Prodrug: is a pharmacologically inactive
compound that is converted into an active drug
by metabolic transformations.
Soft drug (antedrug): is pharmacologically
active drug that will be metabolized to
terminate its action and facilitate excretion.
1.
2.
3.
4.
Improving aq. Solubility
Improving absorption and distribution
Site specificity: depends on the presence of
certain enzyme that will release the active
form of drug at the site of action
Increase biological stability: mainly by
interfering with drug metabolism
5. Minimize possible toxicity:
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Unpleasant taste or odor
Gastric irritation
Pain at the site of injection
6. Improving patient compliance
7. Solve some formulation problems
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Carrier-linked: here the drug is linked to a
carrier group that can be removed
enzymatically:
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Bipartate: if the drug is directly attached to the
carrier group
Tripartate: if there is a linker group between the
drug and the carrier moiety
Mutual prodrug: here two drugs are linked together,
they are synergistic to each other
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Bioprecursor:

Compound that is metabolized by molecular
modification into either an active form or into an
intermediate that will be farther metabolized.

Here oxidation is the main metabolic
biotransformation involved in the activation of
bioprecursors

Drugs with alcohol and carboxylic acid groups:

The common carrier group is the ester (WHY?)
 Availability of esterase enzyme
 Possible of either increasing or decreasing the
lipophilicity of the parent drug.
 Can be either easily hydrolyzed or relatively stable
ester
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Small sized esters will be easily hydrolyzed
than sterically hindered esters
Electronic factor may play a role in the rate of
hydrolysis:

Drugs having carboxylic acid group can be
esterified to:
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Increase lipophilicity.
Increase Pka: this can be done by making the choline
ester of these drugs:
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The amide derivative is not a suitable choice in
most of the case (WHY?)….Stable bond toward
hydrolysis compared to the ester bond.

Some are more susceptible to cleavage:
 Amides of amino acids.
 Phenyl carbamate

amine prodrugs might have lowered
Pka…lower ionization… more lipophilic than
the parent drug, the followings are examples of
some lipophilic prodrugs from amine:
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Prodrugs to increase water solubility:

Esters with anionic solubilizing agent are poorly
hydrolyzed while with cationic solubilizing groups
will be easily hydrolyzed
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Prodrugs to increase water solubility:

Prodrugs to improve absorption through
biological membranes:

Prodrugs to improve absorption through
biological membranes:

Prodrugs for site specificity:
Increasing lipophilicity will increase the access to
almost all tissues.
 Factors affecting the penetration though BBB:

 Molecular size.
 Lipophilicity
 Stability toward enzymes available in BBB
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Prodrugs for site specificity:
 Progabide is an example.. Will b e hydrolyzed after
passing the BBB.
 Tumor cells have elevated amount of phosphatase and
amidase.

Prodrugs for site specificity:
 Approaches of site specific anti-tumor agents:
 Enzyme-prodrug therapy:
 Achieve selective activation of prodrug at a desired site
 Prodrug activating enzyme is incorporated into the target
tumor cells, then the prodrug will be administered
systemically (what are the drawbacks of this approach?)
 Antibody-directed enzyme prodrug therapy:
 An antibody produced against a tumor cell line.
 Then linked to the exogenous activating enzyme.
 This antibody-enzyme complex will be accumulated on
the tumor cells.
 Prodrug will be administered then will be activated once
reaches tumor cells.
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Prodrugs for site specificity:
 Antibody-directed enzyme prodrug therapy:
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Prodrugs for stability:

Either physicochemical stability or biological
stability:
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Prodrugs for stability:
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Prodrugs to decrease ionization in GIT….
Gives better oral availability:
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Prodrugs to improve chemical stability:

Examples are the acid stable penicillins

Prodrugs to improve rectal absorption:
Mainly drugs are absorbed from rectum through
passive diffusion (the same as from intestine)
 Passive diffusion depends on the degree of
lipophilicity and water solubility.
 Little amount of fluid is present in the rectum, this
means that drug must have greater water solubility
in order to be dissolved in rectum.

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Prodrugs to improve ocular delivery:

Problems in ocular delivery:
 Is to attain the optimal drug concentration
 Tear turn-over
 Poor conjunctival absorption due to the specialized
corneal membrane
Only 1-10% of the topically applied treatment to eye
will be absorbed
 LogP of drug administered to eye must be 2-3
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Prodrugs to minimize toxicity:
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Dipifevrin is an example…less toxic than
epinephrine because it will act locally in the ocular
cavity.
Aspirin prodrugs:
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Prodrugs to encourage patient acceptance:
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Prodrugs to eliminate formulation problems:
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Example: formaldehyde is normally used as
antiseptic and disinfectant, but it is highly unstable
and toxic…converted to more stable adamantane:
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Drug here is covalently attached to a
macromolecule such as synthetic polymers,
glycoproteins, lipoproteins, albumin, liposome,
DNA and antibodies.
Advantages:
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Targeting specific target.
Improving therapeutic index and lowering toxicity
Reducing drug metabolism and excretion
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Disadvantages:
Steric hindrance may affect chemical and enzymatic
hydrolysis of drug-macromolecule complex.
 Immunogenic
 Large –sized complex…might not get into the cell,
except by pinocytosis…then drug will be released
after biodegradation by lysosomes.

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By synthetic polymers:

Drug here is attached to totally synthetic polymers
 Sustained release of ibuprofen
 Prolonged anti-inflammatory effect

By synthetic polymers:

Sometimes a spacer is added between the drug and
the macromolecule…to enhance the biodegradation
and the release of drug:

By poly amino acids:
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Here the drug is attached to peptide chain.
The advantage is the biodegradability of the peptide
chain…mainly when the amino acids are in the Lstereochemistry.
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To improve site specificity:
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Solubilizer group such as ionizable hydrophilic group
Homing device….for targeting specific site…such as antibodies

To improve site specificity:
40X less toxic than
nitrogen mustard
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This is used to overcome the problem of too
labile or too stable bipartate prodrugs
Sometimes called double prodrugs.
Here the drug is attached to a linker that is in
turn will attach to the carrier group.
First the carrier will be removed by hydrolysis,
then an unstable intermediate will be
formed…rearranged to release the active drug

The methyl ester did not give the same improvement in absorption and activity
(why?).
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In this delivery system:
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The dyhydropyridine-drug complex will be
lipophilic…better penetrate into the CNS through
BBB.
Then the dihydropyridine will be enzymatically
oxidized to give the pyridinium
ion…ionized…water soluble… trapped within the
CNS.
Then the drug-pyridinium complex will be
hydrolyzed to release the active drug and the non
toxic N-methyl nicotinic acid.
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Peptides are normally coupled to drugs to:
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Improve oral availability
Improve skin penetration
Enhance antibacterial action.
This depends on the fact that cell membranes
have peptide transport integral proteins called
permease that will actively ingest peptides and
peptidomimetic agents into the mammalian
cells as well as bacterial cells.
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Applied when it is necessary for two
synergistic drugs to be at the same time at the
same site.
Mutual prodrug is a bipartate or tripartate
prodrug in which the carrier is the synergistic
drug.

If the two synergistic drugs are given at the
same time but separately, they will not
necessarily reach the same site of action at the
same time.

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Example: the common combination of amoxicillin
and clavulanic acid, or Gentamicin with
Carbenicillin.
Example of mutual drug is sultamicillin
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Bioprecursor prodrugs mostly use either oxidative
or reductive activation reactions.
The main activation pathways are:
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Proton activation.
Hydrolytic activation
Elimination activation
Oxidative activation
Reductive activation
Nucleotide activation
Phosphorylation activation
Sulfation activation
Decarboxylation activation
Isoxazole ring is known to undergo elimination to nitrile

In order to increase the concentration of L-dopa
reaching brain, Peripheral L-amino acid
decarboxylase inhibitor is normally
administered with L-dopa; carbidopa or
benserazid are normally given.

Structure-based drug design:
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The macromolecular target can be isolated and
crystallized…then the structure will be determined
using X-ray crystallography.
This structure will not give information about the
binding site.
The co-crystal structure (structure of protein with
the inhibitor inside) is better (WHY?):
 Where is the active site.
 The distance between inhibitor and binding site
boundaries
 The possible bonds between inhibitor and binding site
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First the inhibitor will be removed from the
active site (in-silico).
Then lead compounds will be inserted
(docked) into the active site to see how they fit.
Best fit compounds will be synthesized and
tested for activity.

Involves the design of a novel drug structure
based on a knowledge of the binding site alone.
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In this approach, you must have good supply of
enzyme.
Sometimes the bacterial version of enzyme will be
used (obtained by recombinant DNA technology).
The major drawback of this, is the bacterial version is
not identical to the human enzyme…. But it can be
considered very similar.