The document discusses the concept of prodrugs. It defines prodrugs as therapeutically inactive compounds that are metabolized into active drug metabolites. The objectives of prodrug design are to overcome barriers like poor solubility, stability, absorption and toxicity. An ideal prodrug is pharmacologically inert, transforms rapidly into the active form at the target site, and produces non-toxic metabolic fragments. Prodrugs are classified based on their structure and site of conversion. The applications of prodrugs include improving drug properties and delivery.

1. By
ASHUTOSH GUPTA
From BIT Mesra Ranchi

2. Content
 Introduction
 History of prodrug
 Prodrug concept
 Objective of prodrug
 Properties of ideal prodrug
 Classification of prodrug
 Limitation of prodrug
 Application
 Reference

3. Introduction
 The concept of prodrug is first introduced by Adrian albert in 1958 to describe
the compound undergo biotransformation prior to eliciting their pharmacological
effect.
 Prodrug is defined as therapeutic agent that are inactive but predictable
transformed into active metabolites.
 Most of the drug available presently have some undesirable side effect that
hamper their therapeutic efficacy.
 A therapeutically active drug may have limited utilization in clinical practices
because of various shortcomings like poor organoleptic properties, poor
bioavailability, short duration of action, non-specificity, incomplete absorption,
poor aqueous solubility, high first-pass metabolism or other adverse effect.

4. History of Prodrugs
• The first compound fulfilling the classical criteria of a prodrug was acetanilide,
introduced into the medical practice by Cahn and Hepp in 1867 as an antipyretic
agent. Acetanilide is hydroxylated to biologically active acetaminophen.
• Another historical prodrug is Aspirin (acetylsalicylic acid), synthesized in 1897 by
Felix Hoffman (Bayer, Germany), and introduced into medicine by Dreser in 1899.
• The prodrug concept was intentionally used for the first time by the Parke-Davis
company for modification of chloramphenicol structure in order to improve the
antibiotic’s bitter taste and poor solubility in water. Twoprodrug forms of
chloramphenicol were synthesized: chloramphenicol sodium succinate with a
good water solubility, and chloramphenicol palmitate used in the form of
suspension in children.

5. Schematic illustration of the prodrug concept

6. Objective of prodrug
• Prodrug design aims at overcoming a number of barriers to a drug’s usefulness.
Barriers objective
 Pharmaceutical
- insufficient chemical stability
- poor solubility
- offensive taste or odour
 Pharmaceutical
- improved formulation
- improved chemical stability
 Pharmacokinetic
- low oral absorption
- marked presystemic metabolism
- short duration of action
 Pharmacokinetic
- improved bioavaliblity
- prolonged duration of action
- improve organ selectivity
 Pharmacodynamic
- toxicity
 Pharmacodynamic
- decreased side effect

7. Properties of ideal prodrug
1.
• Pharmacological Inertness
2.
• Rapid transformation, chemically or enzymatically,
into the active form at the target site
3.
• Non-toxic metabolic fragments followed by
their rapid elimination

8. CLASSIFICATION OF PRODRUG
 Prodrug based on structural association of molecules
• Carrier linked prodrugs
• Tripartite prodrug
• Mutual prodrugs
• Double prodrug
• Bio precursor
- Esters
- Prodrug for amide, imides and acidic compounds
 classification on the basis of sites of conversion into the active drug foam
• Type 1
• Type 2

9. Active Drug
Inert Carrier
Carrier linked prodrug
Chemical Prodrug Formation
Chemical/Enzymatic cleavage
in vivo
Covalent Bond
• Carrier linked prodrug consists of the attachment of a carrier group
to the active drug to alter its physicochemical properties.
• The subsequent enzymatic or non-enzymatic mechanism releases the
active drug moiety.

10. Tripartite prodrug
 Structure of most prodrug is bipartite (having two parts) in nature in which parent
drug is attached directly to promoiety bond.
 In some cases bipartite prodrug may be unstable, the problem can be overcome by
designing a tripartite prodrug ( having three parts).
Drug
linking
structure Carrier

11. Mutual Prodrugs
• A mutual prodrug 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.

12. AspirinParacetamol
Sulbactum
Ampicillin
Benorylate/Benorilate Sultamicillin

13. Polymeric prodrug
 It is also known as macromolecular prodrugs.
 The drug is dispersed or incorporated in the polymer without formation of covalent bond
between the polymer and drug.
Ex:- p-phenylene diamine mustard is covalently attached with polyamino
polymer backbone of polyglutamic acid .
Double prodrug
 In double prodrug concept, prodrug is further derivatized in a fashion such that enzymatic
conversion to prodrug is possible before prodrug can cleave to release active drug, for
example diesters of pilocarpic acid.

14. Bio-precursors
• Bio- precursor prodrugs produce
modification of their inactive form.
their effects after in vivo chemical
• Bio-precursor prodrugs rely on oxidative or reductive activation reactions
unlike the hydrolytic activation of carrier-linked prodrugs.
• They metabolized into a new compound that may itself be active or
further metabolized to an active metabolite

15. Classification based on the site of conversion
 Prodrug also classified into two types on their site of conversion into a active drug
type:
Type 1:- which are converted intracellularly (e.g. anti viral nucleoside analogs, lipid-
lowering statins, antibody directed enzyme prodrug, gene- directed enzyme prodrug))
Type 2:- which are converted extracellularly (e.g. etoposide phosphate,
valganciclovir)

16. Type Converting
site
Subtype Tissue
location of
conversion
Examples
Type I Intracellular Type IA Therapeutic
target
tissue/cells
Zidovudine, 5-
Flurouracil
Type II Intracellular Type IB Metabolic
tissues
(liver/lungs
etc)
Captopril,
cyclophospham
ide
Type II Extracellular Type IIA GI fluid sulfasalazine
Type II Extracellular Type IIB Systemic
circulation
Fosphenytoin,
bembuterol

17. Limitation of prodrug
 Formation of an unexpected metabolism from the total prodrug that may be toxic.
 The inert carrier generated metabolic cleavage may also transform into toxic metabolite.
 Duration its activation stage, the prodrug might consume a vital cell constituent such as
glutathione leading to its depletion.

18. Application
 Improvement of taste
 Change in physical from of drug
 Improvement the odour
 Reduction in GI irritation
 Reduction in pain on injection
 Enhancement of drug solubility and dissolution rate
 Enhancement of chemical stability
 Enhancement of bioavailablity
 Prevention presystemic metabolism
 Prolongation duration of action
 Reduction in toxicity
 Site- specific delivery

19.  Improvement of taste
• The undesirable taste arises due to adequate solubility and interaction of drug with taste
receptors, which can be solved by lowering the solubility of drug or prodrug in saliva.
• Chloramphenicol, an extremely bitter drug has been derivatized to chloramphenicol
palmitate, a sparingly soluble ester.
• It possesses low aqueous solubility which makes it tasteless and later undergoes in vivo
hydrolysis to active chloramphenicol by the action of pancreatic lipase.
 Change in physical form of drug
• Some drugs in liquid foam are not formulation of solid dosage form especially if their dose
is high.
• The method of converting such liquid drugs into solid prodrug involves formation of
symmetrical molecules having a higher tendency to crystallize, for example, esters of
trichloroethanol.

20.  Imrovement of odor
• The ethyl mercaptan (tuberculostatic agent) has a boiling point of 25ºC and a strong
disagreeable odour.
• Diethyl dithio isophthalate, a prodrug of ethyl mercaptan has a higher boiling point and is
relatively odourless.
 Reduction in GI irritation
• Several drugs cause irritation and damage to the gastric mucosa through direct
contact, increased stimulation of acid secretion or through interference with
protective mucosal layer.
Drug Prodrug
Salicylic acid Salsalate, Aspirin
Phenylbutazone N-methyl piperazine salt
Nicotinic acid Nicotinic acid hydrazide

21.  Reduction in pain on injection
 Pain caused by intramuscular injection is mainly due to the weakly acidic nature or poor
aqueous solubility of drugs.
 Ex: IM injection of antibiotics like clindamycin and anti convulsant like phenytoin was
found to be painful due to poor solubility. So, prodrugs are produced like 2’phosphate
ester of clindamycin and hydantoic ester prodrug of phenytoin (fosphenytoin) an
aqueous soluble form of phenytoin respectively.
 Inhancement of drug solubility
• The prodrug approach can be used to increase or decrease the solubility of a drug,
depending on its ultimate use.
Example-The solubility of betamethasone in water is 58 μg/ml at 25⁰C. The
solubility of its disodium phosphate ester (a charged ester promoeity) is more than
100 mg/ml, an increase in water solubility greater than 1500-fold.
Acetylated sulfonamide moiety enhanced the aqueous solubility of the poorly water-
soluble sodium salt of the COX-2 inhibitor Parecoxib ~300-fold.

22.  Enhancement of chemical stability
• Chemical stability is an utmost necessary parameter for every therapeutic agent.
• The prodrug approach is based on the modification of the functional group responsible for the
instability or by changing the physical properties of the drug resulting in the reduction of
contact between the drug and the media in which it is unstable.
• Ex: Inhibiting the auto aminolysis, which occur due to capability of NH2 group of side chain to
attach β lactam ring of other molecule, in ampicillin molecule in concentrated solution it
generates polymeric species of ampicillin. By making hetacillin, a prodrug of ampicillin
formed by the reaction of acetone and ampicillin „ties up‟ the amine group and thus inhibits
auto aminolysis
 Enhancement of bioavailablity
 Various therapeutic agents such as water soluble vitamins, structural analogues of natural
purine and pyrimidine nucleoside, dopamine, antibiotics like ampicillin and carbenicillin,
phenytoin and cardiac glycoside such as gitoxin suffers with poor gastrointestinal absorption.
 The prime cause of the poor absorption of these agents is their highly polar nature, poor
lipophilicity and/or metabolism during the absorption process.
 On contrary gitoxin, a cardiac glycoside has very poor oral bioavailability due to limited
aqueous solubility

23. • Absorption of water soluble vitamin was enhanced by derivatization of thiolate ion to
form lipid soluble prodrugs .
• Dopamine was made useful by making its precursor L-Dopa. Though L- Dopa is highly
polar, it is actively transported through specific L–amino acid active transport
mechanism and regenerates dopamine by decarboxylation.
• Penta acetyl prodrug of gitoxin has four to five times more aqueous solubility.
• To increase aqueous solubility esterification with amino acids is done. Examples of such
prodrugs are valacyclovir and valgancyclovir, which are valine esters of the antiviral
drugs acyclovir and gancyclovir, respectively.

24.  Prevention presystemic metabolism
 Following oral administration, a drug must pass through two metabolizing organs i.e.,
liver and gastrointestinal mucosa, before reaching the general circulation.
 Phenolic moiety, oxidative N– and O– dealkylation, ester cleavage and peptide
degradation are responsible for the pre-systemic metabolism of various drugs.
 Two types of drugs fall into this category.
 The first are drugs rapidly degraded by the acid condition of the stomach.
 Drugs of second category degrade due to enzymes present in the gastrointestinal
mucosa and liver.

25.  The first pass metabolism of a drug can be prevented if the functional group
susceptible to metabolism is protected temporarily by derivatization.
• Alternatively manipulation of the drug to alter its physicochemical properties may
also alter the drug – enzyme complex formation.
• Naltrexone (treatment of opioid addiction) and is readily absorbed from GIT and
hence undergoes Pre-systemic metabolism. Ester prodrugs such as O-
nitrobenzoate and acetylsalicylate increased bioavailablity 45 and 28 fold
respectively.
Drug Prodrug
Propranolol Propranolol hemisuccinate
Dopamine L-DOPA
Morphine Heroin

26.  Prolongation of duration of action
• Drugs with short half life require frequent dosing with conventional dosage
forms to maintain adequate plasma concentration of the particular drug.
• In plasma level time profile and consequently patient compliance is often poor.
• Prolongation of duration of action of a drug can be accomplished by the prodrug .
Prodrug can be formed by two approaches-
To control the release of prodrug
Drug Ester Prodrug
Testosterone Testosterone propionate
Estradiol Estradiol propionate
Fluphenazine Fluphenazine deaconate

27.  Reduction of toxicity
• An important objective of drug design is to develop a moiety with high activity and low
toxicity
• NSAIDs local side effects like gastric distress with various, which can be overcome by
prodrug design.
• Another example is the bioprecursor Sulindac, as it is a sulphoxide, it doesn’t cause any
gastric irritation and also better absorbed.
• The prodrug Ibuterol is diisobutyrate ester of Terbutaline (a selective β-agonist
useful) in glaucoma. This prodrug, is 100 times more potent, has longer duration of
action and is free from both local and systemic toxicity.

28.  Site specific drug delivery
• After its absorption into the systemic circulation, the drug is distributed to the various
parts of the body including the target site as well as the non-target tissue.
• These problems can be overcome by targeting the drug specifically to its site of
action by prodrug design
• The prodrug is converted into its active form only in the target organ/tissue by utilizing
either specific enzymes or a pH value different from the normal pH for activation e.g. 5-
amino salicylic acid.

29.  References
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effects, International Journal of Medical and Pharmaceutical Sciences, Vol 1, Issue 7, Pg.
No. 1-13, 2011.
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Challenge for the Drug Development, Pharmacological Reports, 65, Pg. No. 1-14, 2013.
• Arik Dahan, Ellen M. Zimmermann and Shimon Ben-Shabat, Modern Prodrug
Design for Targeted Oral Drug Delivery, Molecules, 19, Pg. No. 16489-16505,
2014.
• Jarkko Rautio, Hanna Kumpulainen, Tycho Heimbach, Reza Oliyai§, Dooman Oh|,
Tomi Järvinen and Jouko Savolainen, Prodrugs: design and clinical applications,
Nature Reviews: Drug Discovery, Vol.7, Pg. No.255-270, March 2008.
• Longqin Hu, The prodrug approach to better targeting,Pg. No. 28-32 August 2004.
• V.S. Tegeli, Y.S. Thorat, G.K. Chougule, U.S. Shivsharan, G.B. Gajeli, S.T. Kumbhar,
Concepts and Advances In Prodrug Technology, International Journal of Drug
Formulation & Research, Vol. 1(iii), Pg.No. 32-57, Nov.-Dec. 2010.

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