2. Prodrug : Introduction
A prodrug is defined as a biologically inactive derivative of a
parent drug molecule that usually requires a chemical or
enzymatic transformation within the body to release the
active drug, and possess improved delivery properties over
the parent molecule.
The concept of Prodrug was first introduced by
Adrian Albert in 1958.
The development of prodrugs is now well established as a
strategy to improve the physicochemical, biopharmaceutical
or pharmacokinetic properties of pharmacologically potent
compounds, and thereby increase usefulness of a potential
drug.
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4. Properties of
Ideal Prodrug
Pharmacological Inertness
Rapid transformation, chemically or
enzymatically, into the active form at the
target site
Non-toxic metabolic fragments followed
by their rapid elimination
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6. 1. Carrier Linked Prodrug
Carrier linked prodrug consists of the attachment of a carrier
group to the active drug to alter its physicochemical
properties.
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7. 1 (a). Bipartite Prodrug
It is composed of one carrier (group) attached to the drugs.
Such prodrugs have greatly modified lipophilicity due to the
attached carrier. The active drug is released by hydrolytic
cleavage either chemically or enzymatically.
E.g. Tolmetin-Glycine Prodrug.
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8. 1 (b). Tripartitate Prodrug
The carrier group is attached via linker/spacer to drug.
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9. 1 (c). Mutual Prodrugs
It consists of two pharmacologically active agents coupled
together so that each acts as a promoiety for the other agent
and vice versa.
A mutual prodrug is a bipartite or tripartite prodrug in which
the carrier is a synergistic drug with the drug to which it is
linked.
Benorylate is a mutual prodrug aspirin and paracetamol.
Sultamicillin, which on hydrolysis by an esterase produces
ampicillin & sulbactum.
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10. .
2. Bio-Precursors
Prodrugs
3. Polyymeric
Prodrugs
The bioprecursor does not
contain a temporary linkage
between the active drug and
carrier moiety, but designed from
a molecular modification of an
active principle itself.
Eg.: Phenylbutazone gets
metabolized to oxyphenbutazone
that is responsible for the anti
inflammatory activity of the
parent drug
Also known as macromolecular
prodrug, the drug is dispersed or
incorporated into the polymer
(both naturally occurring and
synthetically prepared) system
without formation of covalent
bond between drug and polymer.
Eg: p–phenylene diamine
mustard is covalently attached to
polyamino polymer backbone
polyglutamic acid.
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11. PRODRUG
Advantages Disadvantages
1. It reduces adverse effects of drug.
2. Drug can be targeted to the
desired sites.
3. Synergistic effects can be
obtained without side effects.
4. Give additional biological action
as that of parent drug.
1. Formation of toxic metabolites
2. The active doses of two
mutual prodrugs of the same
parent drugs may appear to be
same in rats but may be quite
different in clinical investigations.
3. The prodrug might consume a
vital cell constituent such as
glutathione during its activation
stage which causes depletion of
prodrug.
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12. Applications of Prodrugs
Pharmaceutical Applications Pharmacokinetic Applications
Masking Taste or Odour
Reduction of gastric irritation
Reduction in Pain at Site of
Injection
Enhancement of drug solubility
and dissolution rate
Enhancement of chemical
stability
Increase in patient compliance
Enhancement of
Bioavailablity
Prevention of Presystemic
metabolism
Prolongation of duration of
action
Reduction Local and
Systemic Toxicity of Drugs
Site Specific Drug Delivery
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13. Site Specific Drug Delivery
Site Specific Drug Delivery in Chemotherapy
Directed Enzyme Prodrug Therapy (DEPT)
Many chemotherapy drugs for cancer lack tumour specificity
and the doses required to reach therapeutic levels in the
tumour are often toxic to other tissues.
(DEPT) uses enzymes artificially introduced into the
body to convert Prodrugs, which have no or poor biological
activity, to the active form in the desired location within the
body.
DEPT strategies are an experimental method of reducing the
systemic toxicity of a drug, by achieving high levels of the
active drug only at the desired site.
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17. Clostridia-directed Enzyme
Prodrug Therapy (CDEPT)
CDEPT is the use of Clostridia to convert prodrugs into active drug agents.
CDEPT exploits the hypoxic environment of solid tumors to target drugs to
tumors using anaerobic bacteria resident in the tumour to convert the pro-drug
to the active form.
Solid tumours, in contrast to normal tissues, grow rapidly. As a result, the
cancerous tissues may suffer from inadequate blood and oxygen supply.
Therefore, clostridia can grow in tumor and destroy it specifically.
In CDEPT, a prodrug-converting enzyme expressed by a clostridial expression
plasmid converts a prodrug into an active drug form within the tumor.
While the prodrug is the inactive form and can be administrated to the blood,
the products of the prodrug cleavage are highly cytotoxic and show their effect
only in the vicinity of tumor cells.
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18. Novel Approaches for Prodrug
The colloidal drug delivery system works as a controlled and sustained
delivery by releasing the encapsulated drug while in circulation or
after the recognition by cell, so it is necessary that the delivery system
must contain maximum quantity of drug for optimum efficacy.
The encapsulation depends upon the physicochemical properties
which can suitably modified by linking with promoiety and altering as
prodrug.
Encapsulation can be achieved by accepting any of below method:
i. Liposomes: it consist of lipid bilayer in which between lipid bilayer
intervening water molecules are prsent
ii. Solid Lipid Nanoparticles: it consist of high melting point
trigyleceride as the ssolid core and a phospholipids coating
iii. Emulsions: oil in water emulsion in used as sustained drug delivery
system
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19. Examples of Prodrug
PARENT DRUG PRODRUG
ACTIVE DRUG PRODRUG
Sulfanilamide Protonsil
Dopamine Levodopa
Ampicillin Talampicillin
Oxazepam Diazepam
Mercaptopurine Azathioprine
Hydrocorticosone Cortisone
Adrenaline Dipiverfin
Predinsolone Prednisone
Enalprilat Enalpril
Phosphoramide mustard Cyclophosphamide
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20. Prodrug: The Conclusion
Prodrug design is a part of the general
drug discovery process, in which a
unique combination of therapeutically
active substances is observed to have
desirable pharmacological effects.
In human therapy prodrug
designing has given successful
results in overcoming
undesirable properties like
absorption, nonspecificity, and
poor bioavailability and GI
toxicity.
Thus, prodrug approach
offers a wide range of options
in drug design and delivery
for improving the clinical and
therapeutic effectiveness of
drug.
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