Definition of prodrugs along with their uses in pharmacy have been discusses here in brief. Also includes the basic objectives of their formulation with examples.

1. BASIC CONCEPT OF PRODRUG & THEIR
APPLICATION IN PHARMACY FIELDS
NAME OF STUDENT – SHUVAM SAR
ROLL NUMBER – 19320219008
MOBILE NUMBER - +918478098881
EMAIL ID – itzshuvam@gmail.com

2. ABSTRACT – Prodrugs are formulated to get the desired effects of any drug molecule, to
achieve highest safety & efficacy with least toxicity, elevated taste & smell, to by pass the
biotransformation related wastage of drug quantity within the body after administration through
any route. Other goals of prodrug formulation include, getting better patient compliance with
lesser GIT irritation, better distribution profile, enhanced permeability & absorption.
KEYWORDS – Prodrugs, efficacy, biotransformation, patient compliance,
distribution profile
REPORT –
Definition - Prodrugs are bioreversible derivatives of drug molecules which undergo chemical
transformation or enzymatic conversion in vivo to release the active parent drug which shows
desired pharmacologic effect.
Objectives of Prodrug design –
Pharmaceutical objectives - To improve solubility (corticosteroids), chemical stability
(dopamine), patient acceptance (chloramphenicol palmitate); to decrease pain & irritation.
Pharmacokinetic objectives – To improve oral absorption/ permeability & bioavailability
(ampicillin), decrease first pass metabolism (propranolol), provide organ/ tissue selective
delivery of active principle.
Pharmacodynamic objectives – To avoid toxicities/ adverse reactions, improve site specificity,
mask reactive species to improve its therapeutic efficacy.
Ideal Prodrugs Should Possess Following Properties –
1. It should not have intrinsic pharmacological activity
2. It should rapidly transform chemically/ enzymatically into active form.
3. The metabolic fragments apart from active drug should be non-toxic.
APPLICATION –
Pharmaceutical application – Improvement of taste, odor; Reduction of GI irritation & pain on
injection; Enhancement of chemical stability of drug & drug solubility of dissolution rate
(hydrophilicty of drugs).
Pharmacokinetic application – Enhancement of bioavailability (lipophilicity), Prolong duration
of action, reduce toxicity, site specific drug delivery (drug targeting), prevention of presystemic
metabolism.

3. Examples – Aspirin – Salicylic acid (reduced GI irritation); Hexamine – Formaldehyde (acts as a
urinary tract antibacterial)
Types of prodrug –
Mutual Prodrug: - A mutual prodrug consists of two pharmacologically active agents coupled
together so that each acts as a promoter for other agents & vice versa. E.g. - Benorylate (NSAID)
= Aspirin + Paracetamol (Prodrug).
Macromolecular Prodrugs: - where macromolecules like polysaccharides, dextrans, proteins,
peptides, polymers are used as carriers.
Site Specific Prodrugs: - Where a carrier acts as a transporter of the active drug to a specific
targeted site.
Figure – Site specific prodrugs
Carrier linked prodrugs/ simple prodrugs: - Where active drug is covalently linked to inert carrier
or transport moiety (ester/ amides). Such prodrugs have greatly modified lipophilicity due to
attached carrier. The active drug is released by hydrolytic cleavage (chemically/ enzymatically).
Bio precursors/ metabolic processes: - Inert molecules obtained by chemical modification of
active drug, but don’t contain a carrier. Mixed type prodrugs are also possible.

4. Figure – Metabolic transformation of prodrug to drug
APPLICATION OF PRODRUG IN PHARMACY FIELD –
1. Improving formulation & administration :-
Dissolution of drug molecule from dosage form may be rate limiting step for absorption.
Different formulation techniques like salt formation & solubilizing excipients have been used to
improve the formulation. Rather prodrug formulations are alternative way to increase the
aqueous solubility of parent drug molecule by improving dissolution rate via attaching ionizable/
polar neutral groups such as phosphates, sugar moieties & amino acids, resulting in enhanced
bioavailability. Phosphate esters are a widely used prodrug for improving aqueous solubility &
parenteral administration. E.g. prednisolone sodium phosphate is a classic example of a
phosphate prodrug. It is highly soluble (more than 30 times greater than prednisolone). Oral
liquid formulation used as immunosuppressant for allergic inflammatory condition in children &
used to mask the unpalatable taste of prednisolone tablets. The phosphate pro moiety is linked
directly to free hydroxyl group on prednisolone.
Another example is about phenytoin. Fosphenytoin sodium salt, the phosphate ester is attached
to acidic amine of phenytoin (antiepileptic agents) via oxymethylene spacer. Fosphenytoin is

5. used to reduce drug precipitation & consequent local irritation by phenytoin at injection site. It
has aqueous solubility more than 7000 times than that of phenytoin & is rapidly converted to
phenytoin in blood. Amino acid esters/ amides are commonly used for ionizable groups.
2. Enhancing permeability & absorption –
The transport of a drug to its site of action usually requires passage through several lipid
membranes. In oral drug delivery, the most common absorption routes are passive transport
mechanism. It has been achieved by masking polar ionized/ nonionized functional groups to
enhance oral/ topical absorption. A hydrophobic hydroxyl, thiol, carboxyl, phosphate, amino
sugar group on parent drug can be converted to more lipophilic alkyl or aryl esters. E.g.
Oseltamivir is an orally active ethyl ester prodrug of selective inhibitor of viral neuraminidase
glycoprotein & used in treatment of influenza type A & type B. After absorption, Oseltamivir
undergoes rapid bioconversion to its parent drug mostly by action of carboxyl esterase.
Prodrugs with lipophilic pro moieties have been used to improve topical absorption for
transdermal & ocular drugs. The stratum corneum, the outermost layer of epidermis represents a
high resistance barrier against topical drug delivery. Only the drug with balance of both water &
lipid solubility can efficiently penetrate through the layer of skin. E.g. tazarotene is an ethyl ester

6. prodrug with enhanced transdermal drug delivery. Tazarotene is used for psoriasis & acne
treatment and causes lesser skin irritation than parent drug tazarotenic acid.
3. Changing the distribution profile –
After administration a drug molecule has to bypass several pharmaceutical & pharmacokinetic
barriers before reaching its physiological target & exert desired effect. Some drugs are to
accumulate into specific tissue/ organ only to improve the efficacy of the drug. E.g. the
antiparkinson agent 2 DOPA, because of its hydrophilic nature, the neurotransmitter dopamine is
not able to cross the blood brain barrier & distribute into brain tissue. However, the alpha amino
acid prodrug of dopamine, 2 DOPA enables the uptake & accumulation of dopamine into brain
via L-type amino acid transporter 1. After L-type amino acid transporter 1 mediated uptake L
DOPA is bio activated by aromatic L amino acid decarboxylase to hydrophilic dopamine, which
is concentrated in dopaminergic nerves.
4. Protecting from rapid metabolism & excretion –
Presystemic metabolism (first pass effect) in the GIT & liver may greatly reduce the total amount
of active drug reaching the systemic circulation & its target. This problem has been by passed by
sublingual or buccal administration or by modified/ controlled release formulation. Rapid
metabolic breakdown of drug can also be protected by prodrug structure. This is carried out by
masking the metabolically labile but pharmacologically essential functional groups. E.g.
bronchodilator & beta 2 agonist terbutaline, sustained drug action has been achieved by
converting its phenolic group. Which are susceptible to rapid & extensive presystemic
metabolism into bis dimethyl carbamates. This prodrug bambuterol is slowly bioactivated to
terbutaline by nonspecific butyrylcholinesterase mainly outside the lungs. As a result slower

7. release & prolonged action, once daily administration of bambuterol provides relief from asthma,
with lower adverse effects than terbutaline.
5. Overcoming toxicity problems –
Adverse drug reactions can change the structure of function of cells/ tissues of organs. Reduced
toxicity can sometimes be accomplished by altering one or more ADME barriers. It is achieved
by targeting drugs to desired cells & tissues via site selective drug delivery. E.g. tirapazamine, a
heteroaromatic nitrogen oxide is a well-known example of hypoxia activated anticancer drugs
which has served as a lead composed in the development of a number of newer prodrugs with
improved anticancer properties. TPZ is bioactivated by a one electron bireduction primarily by
NADPH cytochrome P450 reductase to a highly DNA reactive radical.
6. Improvement of odour –
The odour of a compound depend upon its vapour pressure(boiling point). A liquid with high
vapour pressure(low boiling point) will have a strong odour. Ethyl marcaptan is such drug which
is a foul smelling liquid BP 35c. It is used in treatment of leprosy. Ethyl mercaptan is converted
into its phthalate ester(b.p is high & odour less). The prodrug is administered by rubbing on skin.
7. Reduction of GI irritation –
Different drugs causes irritation & damage to gastric mucosa through direct contact. Increased
stimulation of acid secretion. The NSAIDs, salicylates have such a tendency. They lower gastric

8. pH & induce or aggregate ulceration. E.g. Salicylic acid --- Aspirin; Kanamycin --- Kanamycin
pamoate.
8. Improvement of taste –
Decreasing water solubility of a drug by the formation of a prodrug may have additional benefits
beyond simply increasing absorption. A number of agents have unpleasant taste when the drug
begins to dissolve in mouth & then is capable of interacting with taste receptors. This can present
significant problem mainly in pediatric patients. A prodrug with reduced water solubility does
not dissolve to any appreciable extent in mouth & does not interact with taste receptors. This
approach has been used in case of antibacterial chloramphenicol which produces a bitter taste
when given as parent drug. The hydrophobic palmitate ester does not dissolve to any appreciable
extent in mouth so there is little chance for interaction with taste receptors. The ester moiety is
subsequently hydrolyzed in GIT & the agent is absorbed as chloramphenicol. E.g.
Chloramphenicol palmitate, clindamycin palmitate, erythromycin estolate.
SITE SPECIFIC DRUG DELIVERY (DRUG TARGETING) –
Getting absorbed into systemic circulation, the drug is distributed to target site and non-target as
well. Such a distribution pattern has several disadvantages like – undesirable toxic effects in non-
target tissues, may get eliminated without reaching site of action for having long distribution
time and may not penetrate the target despite reaching them. These problems can be solved by
targeting the drug to its site of action by altering its disposition characteristics. The prodrug is
converted to its active form only in the target organ/ tissue by specific enzymes or pH value,
different from normal value for activation. E.g.
 Acyclovir, the antiviral drug, useful in herpes infections. After entering the infected cell,
the drug is treated with viral enzyme thymidine kinase to form acyclovir monophosphate
that can’t diffuse back out of cell. The monophosphate is further converted to active
triphosphate form by cellular enzymes. The triphosphate then destroys the viral DNA.

9.  Mesalamine/ mesalazine (5 amino salicylic acid) is a drug used in the treatment of
inflammatory bowel disease (ulcerative colitis) since it is not absorbed into systemic
circulation. If it is taken orally, the drug is inactivated before reaching lower intestine, the
site of action. Covalent binding of this agent to sulfapyridine yields prodrug
sulfasalazine, azo compound. This prodrug reaches the colon intact where cleavage by
bacterial enzyme azo reductase release active mesalamine for local action. A
disadvantage for the carrier moiety is its systemic toxicity.
 Hexamine/ methenamine is a prodrug of urinary tract antiseptic, formaldehyde.
Methenamine is administered in enteric coated capsule to protect it from premature
hydrolysis in acidic environment of stomach. After dissolution of enteric coated capsules
in intestine, the agent is absorbed & moves into blood stream, eventually ending up
where acidic pH catalyzes the chemical hydrolysis to give formaldehyde.

10.  The prodrug form of 2PAM (pro 2PAM) an important antidote for phosphate &
carbamate. Acetyl cholinesterase inhibitors used in insecticides & nerve gases. The polar
properties of 2PAM, a permanent cationic species, prevent this drug from being absorbed
following oral administration & restrict drug from access to brain, even after IV. Pro
2PAM is a dihydropiridine derivative that undergoes metabolic & chemical oxidation to
yield active drug 2PAM. The non-ionic pro 2PAM can easily cross blood brain barrier &
oxidation to 2PAM within the brain essentially traps the active cationic drug species
inside the brain.
 Dopamine, a neurotransmitter produces vasodilation of renal tissue by binding to specific
receptors in kidney & used to treat renal hypertension. However, the therapeutic index of
dopamine is small as it precipitates high B.P. by interacting with α-adrenergic receptors.
This can be overcome by taking advantage of the fact that the γ-glutamyl derivatives of
amino acid & peptides selectively accumulate in kidneys. Such a derivative of dopamine,
on reaching kidneys is acted upon successively by 2 enzymes, present in high
concentration in renal tissues, γ-glutamyl trans peptidase & L-aromatic amino acid
decarboxylase to release the active drug dopamine locally. The increase in dopamine
levels produces a marked increase in renal blood flow.

11. CONCLUSION – Still further research works are undergone to formulate most suitable prodrug
for selective drug molecules, with enhanced & selective delivery of drug at the target site.