Asian J. Research Chem. 2(2): April.

-June, 2009
,

ISSN 0974-4169 www.ajrconline.org

REVIEW ARTICLE

Prodrug as a chemical delivery system: A Review

Alka Verma1, Bhupesh Verma1, Sunil Kumar Prajapati2 and Kishu Tripathi3
1
Saroj Institute of Technology and Management, Lucknow (UP) India
2
Department of Pharmacy, Bundelkhand University, Jhansi (UP) India
3
Surya College of Pharmacy, Lucknow (UP) India

Abstract
The development of prodrugs promises to be very effective method for treatment of diseases in future. This approach
has several advantages over conventional drug administration. Prodrugs design to maximize the amount of an active
drug reaching its target through changing the physicochemical, biopharmaceutical or pharmacokinetic properties of
drugs. It also includes characteristics development and classification, effect of prodrug on solubility, permeability
and targeted challenge.

Key words: Prodrug, delivery system

INTRODUCTION: Why to use Prodrugs?

Almost all drugs possesses some undesirable a) Improve patient acceptability (decrease pain on
physicochemical and biological properties. Their injection)
therapeutic efficacy can be improved by minimizing or b) Alter or improve absorption.
eliminating the undesirable properties while retaining c) Alter biodistribution.
the desirable one’s. This can be achieved through d) Alter metabolism
biological, physical or chemical means. e) Alter elimination.6
• The biological approach is to alter the route of
administration which may or may not be acceptable to Characteristics of Prodrugs
patient. In recent years numerous prodrugs have been designed
• The physical approach is to modify the design of and developed to overcome barriers to drug utilization
dosage form such as controlled drug delivery of drug. such as:
• The third and best approach in enhancing drug • Low oral absorption properties
selectivity while minimizing toxicity, is the chemical • Lack of site specificity
approach for design of prodrugs.1,2,3 • Chemical instability
• Toxicity
What is Prodrug? • Bad taste
The term prodrug refers to a pharmacologically inactive • Bad odour
compound that is converted to an active drug by a • Pain at application site 7,8,9
metabolic biotransformation which may occur prior,
during and after absorption or at specific target sites The following characteristics of prodrugs must be
within the body.4 improved for site specific drug delivery:
According to IUPAC (International Union of pure and • The prodrug must be readily transported to site of
applied chemistry): action.
Prodrug is defined as any compound that undergoes • The prodrug must be selectively cleaved to active drug
biotransformation before exhibiting its pharmacological utilizing specific enzymes.
effects. 5 • Once prodrug is selectively generated at site of action,
the tissue must retain the active drug without further
degradation.

Received on 16.12.2008 Modified on 12.05.2009

Accepted on 02.06.2009 © AJRC All right reserved
Asian J. Research Chem. 2(2): April.-June, 2009 page 100-103

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Classification of Prodrugs
A) Carrier linked prodrug:
• Contain a group that can be easily removed
enzymatically (such as ester) to reveal the true drugs.
• Ideally the group removed is pharmacologically
inactive and nontoxic while the connecting bond must be
labile for efficient activation in vivo.
Prodrugs are the ones where the active drug is covalently
linked to an inert carrier transport moiety. They are
generally esters or amides. Such prodrugs have greatly
modified lipophilicity due to the attached carrier and the
active drug is released by hydrolytic cleavage, either
chemically or enzymically. It can be further subdivided
into-
Bipartate- Composed of one carrier (group) attached to
the drugs.
Tripartat- Carrier group is attached via linker to drug.
Mutual Prodrugs- Two drugs linked together.
B) Bioprecursors:
Metabolized into a new compound that may itself be
active or further metabolized to an active metabolite
(e.g. amine to aldehyde to carboxylic acid) 10.
Site specificity:
The most important feature of efficient drug is right site
of action. It is necessary to deliver the drug precisely to
the affected part of body, where it is supposed to be
attacked.
• At least three following factors should be optimized to
obtain a prodrug acting at specific site:
1)Prodrug must be directly transported to the site of
action, and uptake at the site must be rapid and
essentially perfusion rate must be limited.
2) Once the prodrug reaches the site of its action, it must
be selectively cleaved yielding the active drug, relative
to its conversion at other sites.
3) Once selectively generated at site of action, the active
drug must be retained by tissue.11
Solution-
These problems can be overcome by:
• Targeting the drug to its site of action by altering its
disposition characteristic.
• There are several approaches to drug targeting and
prodrug design is one of them.12
For site specificity:
1. Selective uptake system
Dopamine,a neurotransmitter, produce Vasodilation of
renal tissue by binding to specific receptor in kidney and
this can be used to treat renal hypertension. However,
the therapeutic index of dopamine is small as it
precipitates high blood pressure by interaction with -
adrenergic receptor. This can be overcome by taking
advantage of fact that -gultamyl derivatives of amino
acid and peptides selectively accumulates in kidney.
Such a derivative of dopamine, on reaching the kidney it
is acted upon successively by two enzymes that are
present in high concentration in renal tissue, - glutamyl
transpeptidase and L-aromatic amino acid decarboxylase
to release the active drug dopamine locally. This
increase in dopamine levels produces a marked increase
in renal blood flow.Same principle can be used to
deliver sulfonamides selectively to kidneys, the prodrug
used are M-acyl- -glutamyl Sulfonamides.13,14,15,16
(2) For Urinary tract infection:
Hexamine is a stable inactive compound at pH greater
than 5. However, in mere acidic pH, the compound
disintegrate spontaneously to form formaldehyde, which
has antibacterial properties.This is useful for treatment
of urinary tract infections. The normal pH of blood is
slightly alkaline and so the drug circulate in the body as
unchanged. However,once it is excreted into urinary
tract, it encounters urine, which is acidic as a result of
bacterial infection. 17
(3) Anticancer chemotherapeutic agent:
These are cytotoxic because they attack growing normal
cells. An example of site specific prodrug is diethyl
stilbestrol diphosphate, which is designed for treatment
of breast cancer.
The site specific delivery can be obtained by tissue
specific activation of the prodrug which results of
metabolism by an enzyme that is either unique for tissue
or present at higher concentration if we compare with
other tissues.
The example of prodrug, whose design is based on site
specific conditions such as lack of oxygen in cells i.e
hypoxic cells,is trapazamine (TPZ) is a bioreductive
drug that exhibits greatly enhanced cytotoxicity in
hypoxic cells, which are frequently radiation resistant
and chemoresistant.
TPZ exhibits particularly good activity when combined
with alkylating agent such as cyclophosphamide (CPA)
These findings suggests the potential benefit of
incorporating TPZ, and perhaps, other bioreductive
drugs into a P450/P480 reductase based gene therapy
strategy for cancer treatment18..
Stability and Resistance
The drug must be resistant to degradation in different
body parts and fluids. L-DOPA is the most important
prodrug that is used in treatment of Parkinson’s diseases.
It is the biological precursor of Dopamine and may be
considered, to be a prodrug. The increased oral
bioavailability of catecholamine, while retaining the
catecholamine itself as an active component, is achieved
by protection of hydroxyl and amino groups. The
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protecting groups are designed to be less susceptible to
metabolism and to gradual dissociation from the
catecholamine molecule in-vivo. There are also other
prodrugs of Dopamine and of analogues of
catecholamine, designed to cross the blood brain barriers
(BBB) and to centrally undergo slow hydrolysis to give
the active species. The hydroxyl groups on the catechol
ring are usually protected by formation of di-o-pivaloyl
or di-o-benzoyl esters.
The antibacterial agent ampicillin is decomposed
because of the intermolecular attack of side chain amino
group on the lactam ring. The prodrugs Hetacillin lock
up the offending amino group in -ring and prevents
decomposition reaction by bacterial -lactamases. Once
the drug has been administered, the drug undergoes
hydrolysis on its own to release ampicillin and acetone.19
Prodrug may protect a drug from first pass effects,
propranolol , -blocker and antihypertensive drug, which
suffers, from the first pass elimination resulting in
decreased bioavalibility of oral doses compared to
intravenous injections. One of the major metabolites is
the o-glucuronide. The hemisuccinate ester was designed
to block glucuronide formulation resulting in 8-fold
increase in plasma levels of propanolol.20
Naltrexone (NTX) ,opioid antagonist,used for treatment
of narcotic dependence and alcoholism. Transdermal
NTX delivery is desirable to help to improve patient
compliance in order to increase the delivery rate of NTX
across human skin.21
Toxicity
Derivative of salicylic acids are one of the oldest
example that are characterized by lesser toxicity than
their parent drugs. Salicylic acid is a good pain-killer but
causes gastric irritation and bleeding because of
carboxyl group. It accumulates in the gastric mucosal
cells. Aspirin, esters of salicylic acid,suppresses gastric
irritation. 22
Prodrugs can be used to afford drugs that would be too
toxic to be given directly, a feature of the slow release.
Propanaldehyde is useful for aversion therapy in patients
addicted to alcohol. However, it is a highly irritating
chemical and causes allergic reactions. As an alternative,
a closely related compound, pargyline is used.
The prodrug that is converted to the active drug at the
target site itself greatly reduced side effects of highly
toxic drugs.23
Poor patient Acceptability
Some drugs have a revolting taste. One way to reduce
this problem is to decrease their solubility in water so
that they do not dissolve on the tongue, for e.g the bitter
taste of antibiotic Chloramphenicol can be avoided by
using palmitate ester, which is quickly hydrolyzed once
swallowed.24
Mutual Prodrug- A therapeutically significant drug may
have limited utilization in clinical practice because of
poor organoleptic properties, poor bioavailability etc.
Mutual prodrug is a type of carrier linked prodrug,
where carrier used in is another biologically active drug
instead of some inert molecule. A mutual prodrug
consist of two pharmacologically active agents coupled
together so that each act as a promoiety for the other
agent and vice versa.
Mutual prodrug design is really do not differ from
general drug discovery process in which a unique
substance is observed to have desirable pharmacological
effects, and studies of its properties lead to the design of
better drugs.25
CONCLUSION
Site specificity is central to the prodrug development
strategy. Even though at present prodrug are not
prevalent in clinical use, in future there will be prodrugs
for every known drug to make them effective in
treatment drug discovery and prodrug development
appear to be complementary for the generation of target
specific medicines of future.
At present the research in this area is at a nascent stage
due to lack of information, regarding all enzymes or
receptors, most suitable for targeting purposes. As the
unrevealing of the microbiological details of affected
targets become clear, prodrug development will surely
decrease side/toxic effect of drugs and also trigger
development of more potent primary drugs.
Prodrugs are used to overcome several undesirable
properties in order to achieve the best clinical drug
application.
The newest discoveries of molecular biology provide
essential information about enzymes and carriers
proteins. It is clear from the foregoing that design of
drug cannot be based just on chemical synthesis. Drug
discovery and prodrug and soft drugs development
appears to be complementary for generation of target
specific medicine now and in the future.
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