Prodrug new

prodrug intro to application

1. By:
Ankit sharmA
M.Pharma
2
nd
Sem (P’Cology)
Bhupal Nobles University
Udaipur, Rajasthan

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.
Ankit Sharma Bhupal Nobles University

3. Concept 0f Prodrug
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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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5. Classification of Prodrug
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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.
Ankit Sharma Bhupal Nobles University

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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14. Types of
Directed Enzyme Prodrug
Therapy (DEPT)
Antibody-directed enzyme prodrug therapy (ADEPT)
Gene-directed enzyme prodrug therapy (GDEPT)
Virus-directed enzyme prodrug therapy (VDEPT)
Polymer-directed enzyme prodrug therapy (PDEPT)
Clostridia-directed enzyme prodrug therapy (CDEPT)
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15. Antibody-directed Enzyme
Prodrug Therapy (ADEPT)
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16. Gene-directed Enzyme
Prodrug Therapy (GDEPT)
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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.
Ankit Sharma Bhupal Nobles University

21. Ankit Sharma
Bhupal Nobles University, Udaipur;
Rajasthan