“Prodrug”

Dr. Mohammed Bashar Al- Qazzan

Fifth year
College Of Pharmcy / Bilad Alrafidain University
 Contents :

1. Introduction.
2. Classification of drugs
3. prodrug definition.
4. Reasons behind preparing prodrugs.
5. Types Of Prodrug.
 Introduction
❖ prodrug:
Inactive compound and must be converted into an active species within the biological system. There are a
variety of mechanisms by which this conversion may be accomplished. Generally the conversion to active
form is most often carried out by;
1. Metabolizing enzymes within the body.
2. Chemical means (e.g., hydrolysis or decarboxylation

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 Reasons behind
preparing prodrugs
1. Increase absorption.
2.Alleviation of pain at site of injection if the agent is given parenterally.
3. Elimination of unpleasant taste associated with the drug.
4. Decrease toxicity.
5. Decrease metabolic inactivation.
6. Increase chemical stability.
7. Prolong or shorten the duration of action, whichever is desired in a
particular agent.
8. Alter biodistribution
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 Classification of drugs

•1.Non-Prodrugs
drugs
•2.Prodrugs

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 Non-produg
1- Hard drugs are compounds that are designed to contain the
structural characteristics necessary for pharmacological activity but in a
form that is not susceptible to metabolic or chemical transformation.

➢The main characteristics:

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 Non-produg

2- Soft drugs
are active compounds that after exerting their desired
pharmacological effect are designed to undergo metabolic
inactivation to give a nontoxic product.
Thus soft drugs are considered to be the opposite of prodrugs.

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 Types
Of Prodrug
❑ On Basis Of Structural Association:

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 1-Carrier-linked
prodrugs
• These are drugs that are attached to through metabolically liable
linkage to another molecule, the so-called pro-moiety, which is not
necessary for activity, but may impart some desirable properties to the
drug, such as increase water or lipid solubility, or site directed
delivery.

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 Cont.
❑A well-designed carrier-prodrug satisfies the following criteria:

1) The linkage between the drug substance and the transport moiety is usually
2) a covalent bond.
3) As a rule the prodrug is inactive or less active than the parent compound.
4) The linkage between the parent compound and the transport moiety must be
broken in vivo.
5) The prodrug, as well as the in vivo released transport moiety, must be nontoxic.
6) The generation of the active form must take place with rapid kinetics to ensure
effective drug levels at the site of action and to minimize either direct prodrug
metabolization or gradual drug inactivation.
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 Cont.
❖ An example of such prodrug is chloramphenicol, its administration parenterally may
causes pain at site of injection, especially if a drug begin to precipitate out of solution
and damage the surrounding tissue.
❖ This situation can be remedied by preparing a drug with
increased solubility in the administered solvent .Since
chloramphenicol has low water solubility, the succinate
ester was prepared to increase water solubility of the agent
and facilitate the parenteral administration.

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 Cont.
❖ The succinate ester itself is inactive as an antibacterial agent, so it must be
converted to chloramphenicol for this agent to be effective. This occurs in the
plasma to give the drug and succinate. The ester hydrolysis reaction can be
catalyze by esterase enzyme that present in plasma in large amount.

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 Cont.
➢Prodrugs for Improved Absorption:
• Fluocinolone aceteonide and flucinonide are corticosteroid prodrugs that
allow dermal absorption by “masking” the hydroxyl groups (that can
interact with the skin or binding sites in the keratin) as either esters or
acetonides. Once absorbed through the skin, the true drug is revealed by
esterases or hydrolysis.

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 Cont.
➢Prodrugs for Improved Distribution
• Dipivefrin is a prodrug for the antiglaucoma drug epinephrine. The
dipivaloyl esters allow for greater corneal permeability which are
hydrolyzed by corneal and aqueous humor esterases.

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 Cont.
The ability to prepare ester type prodrugs depends, of course, on the presence
of either a hydroxyl group or a carboxyl moiety in the drug molecule.
The promoiety should be easily and completely removed after it has served
its function and should be nontoxic, as is indeed the case with succinate.
The selection of the appropriate promoiety depends on which properties are
sought for the agent.
If it is desirable to increase water solubility, then a promoiety containing an
ionizable function or numerous polar functional groups is used.
If, on the other hand, the goal is to increase lipid solubility or decrease water
solubility, a nonpolar pro-moiety is appropriate.
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 Mutual
prodrugs
❖Slight variation on the carrier-linked prodrugs approach is seen with mutual prodrugs in
which the carrier also has activity.
❖Estramustine, which is used in the treatment of prostate cancer, provide an example of
this approach. Estramustine composed of phosphorylated steroid (17 ꭤ-estradiol), linked
to normustard [HN(CH2CH2Cl)2] through carbamate linkage.
❖The steroid portion of the molecule helps to concentrate the drug in the prostate, where
hydrolysis occurs to give the normustured and CO2. The normustared then acts as an
alkylating agent and exert a cytotoxic effect.

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 Cont.
❖Slight variation on the carrier-linked prodrugs approach is seen with mutual prodrugs in
which the carrier also has activity.

❖Estramustine, which is used in the treatment of prostate cancer, provide an example of this
approach. Estramustine composed of phosphorylated steroid (17 ꭤ-estradiol), linked to
normustard [HN(CH2CH2Cl)2] through carbamate linkage.

❖The steroid portion of the molecule helps to concentrate the drug in the prostate, where
hydrolysis occurs to give the normustured and CO2. The normustared then acts as an
alkylating agent and exert a cytotoxic effect.

❖ The I 7α-estradiol has an anti androgenic effect on the prostate and thereby, slows the
growth of the cancer cells. Since both the steroid and the mustard possess activity,
estramustine is termed mutual prodrug.
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 Cont.
Phosphorylation of the estradiol can be used to increase the water solubility,
which also constitutes a prodrug modification. Both types of esters (carbamates
and phosphates) are hydrolyzed by chemical or enzymatic means.

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 2-Bioprecursor
prodrugs
• Bioprecursor prodrugs result from a molecular modification of the active
principle generating a new compound, able to be a substrate for the
metabolizing enzymes, the metabolite being the expected active
principle. The bioprecursor-prodrug approach exemplifies the active
metabolite concept in the prospective application.
• In contrast to carrier linked prodrugs, the bioprecursor prodrugs contain
no promoiety, but rather rely on metabolism to introduce the functionality
necessary to crated an active species.
• Example, the NSAID (sulindac) is inactive as the sulfoxide and must be
reduced metabolically to the active sulfide.
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 Cont.
Phosphorylation of the estradiol can be used to increase the water solubility,
which also constitutes a prodrug modification. Both types of esters (carbamates
and phosphates) are hydrolyzed by chemical or enzymatic means.

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 Cont.
Phosphorylation of the estradiol can be used to increase the water solubility,
which also constitutes a prodrug modification. Both types of esters (carbamates
and phosphates) are hydrolyzed by chemical or enzymatic means.

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 Cont.
• Sulindac is administered orally, absorbed in the small intestine, and subsequently
reduced to the active species.
• Administration of the inactive form has the benefit of reducing the gastrointestinal
(GI) irritation associated with the sulfide.
• This example also illustrates one of the problems associated with this approach,
namely, participation of the alternate metabolic paths that may inactive the
compound.
In this case, after absorption of sulindac, irreversible metabolic
oxidation of the sulfoxide to the sulfone can also occur to give an
inactive compound.

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Cont.

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Thank You
For Your Attention