Prodrugs or Drugs Latenation

Albert In 1958 defined the term prodrug as a

pharmacologically inactive cpd that is transformed by the
mammalian system into an active substance by either
chemical or metabolic means.

Harper in 1959 introduced the term

“ Drug Latenation” refer to drugs that were specifically
.designed to require bioactivation
The type of prodrugs to be produced depends on:

1- The specific aspect of drug's action Ʌat requires

improvement and
2- The type of functionality(function grp.) that is
present in Ʌ active drug.

Objective from prodrug to:

1- improve patient acceptability of Ʌ agent
2- reduce pain associated w̄ administration
3-alter absorption.
4-alter distribution,
5- alter metabolism, or
.6- alter elimination
Recently, Ʌ terms hard drugs and soft drugs were
introduced.
Hard drugs: are cpds that are designed to contain Ʌ
structural characteristics necessary for pharmacological
activity but in a form that is not susceptible to metabolic
or chemical transformation.

Characteristics of hard drugs:

• Production of toxic metabolites is avoided
•Increased efficiency of action
• it may be Less readily eliminated
soft drugs: are active cpds that after exerting their
desired pharmacological effect are designed to
undergo metabolic inactivation to give a nontoxic
product.

Thus soft drugs were considered to be

.Ʌ opposite of prodrugs
There r̄ a variety of mechanisms by which this
conversion may be accomplished.
1-most often carried out by metabolizing
enzymes within Ʌ body.
2- by chemical means (e.g.. hydrolysis or
decarboxylation). although this is less
. common
Prodrugs can be grouped into:
1-Carrier-linked prodrugs
2-Bioprecursor prodrugs
3-Mutual prodrugs
 CARRIER-LINKED PRODRUG PRINCIPLE
The drugs that have been attached through a metabolically
labile linkage to another molecule, the so-called promoiety

Drug Chemical synthesis

+
Temporary
Transporter Regeneration in vivo
(Carrier) Prodrug
 The Promoiety(carrier) should be:
- inert not have activity but may impart
some desirable property to Ʌ drug, such
as increased lipid or water solubility or
.site-directed delivery
The aims of promoiety or carrier-linked prodrugs:
- increased absorption.
- alleviation of pain at the site of injection if the agent is
given parenterally (injection site pain relief)

-Elimination unpleasant taste(associated w̄ D)

- decreased toxicity
- decreased metabolic inactivation
- increased chemical stability
- prolonged or shortened action
Chloramphenicol ,wn administration of a drug
parenterally may cause pain at Ʌ site of injection,
especially if Ʌ drug begins to precipitate out of solution
and damage Ʌ surrounding tissue.
This situation can be remedied by preparing a drug w̄
.increased solubility in Ʌ administered solvent
Ʌ succinate ester used is inactive as an

antibacterial agent, so it must be converted to

. chloramphenicol for this agent to be effective

Ʌ 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.
- Ʌ promoiety should be easily and completely removed
after it has served its function and should be nontoxic.
.as is indeed the case w̄ succinate
The selection of the appropriate promoiety depends
on which properties r̄ sought for Ʌ agent.
1- If it is desirable to increase water solubility. Then a
promoiety containing an ionizable function or
numerous polar functional groups is used.
2- If on Ʌ other hand, Ʌ goal is to ↑ lipid solubility or ↓
.water solubility, a nonpolar promoiety is appropriate
Mutual prodrugs
Its carrier-linked prodrug approach in which the carrier
also has activity.
The antineoplastic agent Estramustine, which is used in
the ttt of prostatic cancer,
Estramustine is composed of a phosphorylated steroid
( 17α-estradiol) linked to a normustard [HN(CH 2CH2CI)2]
through acarbamate linkage.
The steroid portion of the molecule helps to concentrate
the drug in the prostate, where hydrolysis occurs to give
the normustard and CO2
Estramustine is termed a mutual
pradrug because both steroid and
mustard possess activity.
Ʌ normustard then acts as an alkylating agent
and exerts a cytotoxic effect.
- 17α-estradiol has an antiandrogenic effect on Ʌ
prostate and therapy, slows Ʌ growth of Ʌ
.cancer cells
Note: phosphorylation of Ʌ estradiol can be
used to increase Ʌ water solubility, which also
constitutes a prodrug modification. Both types of
esters(carbamates and phosphates) r̄ hydrolyzed
.by chemical or enzymatic means
Bioprecursor prodrugs:
In contrast to carrier-linked prodrugs. bioprecursor
prodrugs contain no promoiety but rather rely on
metabolism introduce the functionality necessary
to create an active For example, (NSAID) such
sulindac is inactive as the sulfoxide and must
reduced metabolically to the active sulfide
Sulindac is admini. orally, absorbed in Ʌ
small intestine, & subsequently reduced to Ʌ
active species.
Administration of Ʌ inactive form has Ʌ
benefit of reducing Ʌ gastrointestinal (GI)
.irritation associated w̄ Ʌ sulfide
one of Ʌ problems associated w̄ this approach,
namely, participation of alternate metabolic paths
that may inactivate w̄ cpd. In this case, after
absorption of sulindac, irreversible metabolic
oxidation of Ʌ sulfoxide to Ʌ sulfone can also occur
.to give an inactive cpd
e.g. for chemical activation of prodrug; rely on chemical
mechanisms for conversion of the prodrug to its active
form.
hetacillin is a prodrug form of ampicillin in w̠ Ʌ amide
nitrogen and α-amino functionalities have been allowed
to react w̄ acetone to give an imidazolidinone ring
system .Ʌis ↓es Ʌ basicity of Ʌ α-amino grp and
reduces protonation in Ʌ small intestine so Ʌat Ʌ
.agent is more lipophilic
acetone, must be nontoxic and easily removed *
.after it has performed its function
Prodrugs of functional grps.
Ʌre r̄ a variety of different types of prodrugs. ˄
major types of prodrugs (grouped according to
functional group) and bioprecursor drugs (grouped
according to type of metabolic activation)
Carboxylic Acids and Alcohols:-1
Prodrugs of agents that contain carboxylic acid
or alcohol functionalities can often be prepared
.by conversion to an ester
This is most common type of prodrug
because of Ʌ ease w̄ w̠ ester can be
hydrolyzed to give Ʌ active drug. Hydrolysis
is normally accomplished by esterase
enzymes present in plasma and other
tissues that are capable of hydrolyzing a
.wide variety of ester linkage
a number of the different types of esterases
that prodrugs may use:
*Ester hydrolase
*Lipase
*Cholesterol esterase
*Acetylcholinesterase
*Carboxypeptidase
*Cholinesterase