Presentation on

Antibiotics used as
prodrugs
 Prepared for

Mr. Apurba Sarker Apu

Senior Lecturer

Dept. of Pharmacy

East West University

Prepared by

Tamanna Rahman ID: 2008-1-70-052

Tahmina Khanom ID: 2005-2-70-

006

Abhijit das ID: 2007-1-70-052

Farzana Rahman ID: 2007-1-70-047

Anisur rahman ID: 2006-2-70-108

 What is a Prodrug?
A prodrug is an inactive derivative that will be
converted to the active drug in vivo.

Prodrugs are used when drugs have unattractive

physicochemical properties.

Once administered, the prodrug is metabolised

in vivo into an active metabolite, a process
termed bioactivation
 Why prodrugs are designed

If the drugs have the following properties:

•Physical Properties

 Poor aqueous solubility

Low lipophilicity
Chemical instability
•Pharmacokinetic Properties

Poor distribution across biological

membranes
Good substrate for first-pass metabolism
Rapid absorption/excretion when long-
term effect Desired
Not site-specific
 Why antibiotics are used as
prodrug
Antibiotics constitute a valuable adjunct to the
physicians therapeutic effects in the battle against a
wide variety of infectious diseases. While many
antibiotics can be utilized with a minimum of
modification to ensure their therapeutic effect,
exceptions exist where extensive development must
be undertaken prior to their becoming efficacious
medicinal agents.
Certain shortcomings of these agents, such as lack of
stability or poor bioavailability, can be minimized or
eliminated by the use of carefully designed dosage
formulations. In many instances, however,
formulation development fails to improve those
properties of the antibiotic that are necessary to
ensure therapeutic efficacy. It is in this area that
chemical modification (prodrug formation) of the
parent antibiotic molecule plays an important role.
There are certain drugs that are used as prodrugs.
Such as-
Ampicillin

Carbapenem

Chloramphenicol

Cephalosporins
 Ampicillin

Beta Lactum Antibiotic

Poorly absorbed (30% absorbed)



Show the form of ampicillin that will be observed

in the intestine (pH ~8).
Scientists suggest prodrug forms of
ampicillin that might be better absorbed
after oral dosing.
Ampicillin prodrugs have been designed by
modifying the “R” group in ampicillin
structure
• Objective- to increase lipophilicity.
A number of ampicillin prodrugs have been
synthesized to enhance its oral bioavailability.
Such as-
Pivampicillin
Talampicillin
Bacampicillin
Hetacillin
Breakdown of pivampicillin
within the biologic system
Comparative study between
pivampicllin & ampicillin
The absorption and excretion of equivalent
doses (500 mg) of ampicillin, pivampicillin,
and amoxycillin were compared in 10
healthy volunteers
Comparative study between
pivampicllin & ampicillin (Cont.)

Empty
Stomach

given with
breakfast
Their Mean Half Life was nearly the same

60.9 min for ampicillin

58.4 min for pivampicillin

62.2 min for amoxycillin.

But a significant difference was found in their mean

serum level and cumulative excretion data.
Mean serum level comparison
Cumulative renal excretion
data
By these criteria, pivampicillin was the best-absorbed
drug, with absorption-

3.0 to 3.6 times higher than that of ampicillin

1.2 to 1.5 times higher than that of amoxycillin,

Carbapenem
Carbapenems are the most potent class of β-
lactam antibiotics, which have a broad spectrum
of potent antibacterial activities against Gram-
positive and Gram-negative organisms, including
P. aeruginosa.
 Carbapenems are stable to hydrolysis by various
β-lactamase, and thus, effective against most
cephalosporin-resistant microorganisms.
 Imipenem, panipenem and meropenem
(MEPM) have long been used for serious
infectious diseases, including complicated urinary
tract infection and complicated respiratory tract
infection.
Imipenem and panipenem are unstable
chemically and to renal dehydropeptidase-I,
thus used in combination with cilastatin for
Imipenem and betamipron for panipenem.

MEPM and doripenem have a 1β-methyl group,

and are stable against chemical degradation and
hydrolysis by dehydropeptidase-I and are thus
used without cilastatin or betamipron.
 Carbapenem

Meropenem
Imipenem Panipenem
+ +
(1β-methyl group)
cilastatin betamipron
Meropenem
 Meropenem is an ultra-broad spectrum
injectable antibiotic used to treat a wide
variety of infections, including
meningitis and pneumonia. It is a beta-
lactam and belongs to the subgroup of
carbapenem.
 It is marketed outside Japan by
AstraZeneca with the brand names
Merrem and Meronem. It gained US
FDA approval in July 1996. It penetrates
well into many tissues and body fluids
including the cerebrospinal fluid, bile,
heart valves, lung, and peritoneal fluid.
Tructure activity Relationship
 All these parenteral carbapenems have a carboxyl group at the
carbapene C-3 position, which is essential for interaction with
a target protein, penicillin-binding protein
 A basic group at the pyrrolidine N-1 position, which promote
their invasion through D2 porin into P. aeruginosa, resulting
in little oral absorption because of the two ionizable groups.
Many attempts to find new orally active carbapenems have
been reported, in which the basic group at the pyrrolidine N-1
position was eliminated and the carboxyl group was esterified
by easily hydrolizable promoiety to increase oral absorption,
but most showed very weak antibacterial activity against P.
aeruginosa. carbapenem. Tebipenem showed potent activity
against penicillin-resistant S. pneumoniae, β-lactamase-
negative ampicillin-resistant H. influenzae, H. influenzae and
E. coli;

however, unlike MEPM, tebipenem has no activity
against β-lactamase-producing P. aeruginosa and its
therapeutic use is still limited to pediatric otitis
media, rhinitis and pneumonia. In the present
study, we attempted to increase the oral
bioavailability of MEPM by chemical modification
to a double-promoiety prodrug, because MEPM is
chemically and biologically more stable than
imipenem and panipenem, and has a lower
molecular weight than doripenem. Furthermore, its
efficacy in infection therapy and safety have been
established

Double-promoiety prodrugs of MEPM, in which two

kinds of lipophilic promoieties were introduced at
the carbapene C-3 and pyrrolidine N-1 position of
MEPM to increase oral bioavailability, were
synthesized and biologically evaluated.
 Drug design
First, single-promoiety prodrugs of MEPM were
designed using pivaloyloxymethyl (POM) and 1-
ethylpropyloxycarbonyloxymethyl (EPC).
 β-Lactam antibiotics, such as penicillins,
cephalosporins and carbapenems, have a carboxyl
group that decreases their membrane permeability,
resulting in low oral absorption. In many orally used
penicillins and cephalosporins, their carboxyl group
is esterified with a lipophilic and hydrolyzable
promoiety: these prodrugs are efficiently absorbed
and then rapidly hydrolyzed to an active form.
Second, double-promoiety prodrugs of MEPM were
designed by introduction of the second lipophilic
promoiety to the pyrrolidine N-1 position of MEPM
because no single-promoiety prodrugs of parenteral
carbapenems have been successfully developed, probably
due to their basic side chain, which is also considered to
decrease their membrane permeability. As the second
lipophilic promoiety, carbonate promoieties
(isobutyryloxymethyloxycarbonyl,
propionyloxymethyloxycarbonyl,
butyryloxymethyloxycarbonyl and
valeryloxymethyloxycarbonyl) were used.
The general synthetic routes of prodrugs of MEPM are
shown in All prodrugs were prepared from MEPM.
 Single-promoiety prodrugs were prepared by
esterification with the corresponding alkyl iodides, and
afforded by N-alkylation of pyrrolidine moiety.
Double-promoiety prodrugs were prepared by N-
alkylation and esterification.
Results
Physicochemical properties and oral absorption of single- and double-promoiety
prodrugs of MEPM
The pharmacokinetics of MEPM after oral administration
of compounds was reevaluated to more precisely
determine the parameters:
Blood was taken at 10, 20, 30, 45, 60, 90 and 120 min after
administration.
The Cmax was similar between compounds 4 and 8, and
AUC and bioavailability were slightly higher and T1/2 was
longer in compound
It was confirmed that oral absorption of MEPM was
effectively increased in the double-promoiety prodrugs in
comparison with the corresponding single-promoiety
prodrugs.
Cephalosporins
The cephalosporins
are a class of β- lactum
antibiotic originally
derived from
Acremonium, which
was previously known
as Cephalosporium". 
 
Cefuroxim
Cefuroxime is a second-
generation cephalosporin
antibiotic that has been widely
available in the USA as Ceftin
since 1977. Cefuroxime, like the
penicillins, is a beta-lactam
antibiotic. By binding to
specific penicillin-binding
proteins (PBPs) located inside
the bacterial cell wall, it inhibits
the third and last stage of
bacterial cell wall synthesis.
Cefuroxime-Axetil
 Cefuroxime-Axetil is an ester of cefuroxime,
which can be used as an oral antimicrobial
agent. The prodrug is hydrolysed by
esterases of the gut mucosa, setting free the
active cefuroxime. This second generation
cephalosporin is well known since more
than a decade as a cephalosporin possessing
high stability against gram positive and
gram negative beta-lactamases. Due to its
pharmacokinetic properties and its wide
spectrum of activity, cefuroxime-axetil was
recommended to be used as an oral agent in
bacterial infections of the respiratory tract.
Why the prodrug form is prefered:
Cephalosporins usually exhibit poor bioavailabilities when
they are given orally. Higher values are obtained only with
cephalosporins that are taken up by carrier systems or when
the polarity of the carboxylic acid group in the 4 position is
reduced by esterification . Esterification of the carboxylic
acid group produces derivatives which can be absorbed by
passive diffusion. Therapeutically useful compounds can, however,
be obtained only if the absorbed prodrug ester is readily
converted back to the active drug. The success of the prodrug
ester approach depends vitally on the solubility and lipophilicity
of the prodrug ester as well as its stability to chemical and
enzymatic ester cleavage.
PHARMACOKINETICS
After oral administration, Cefuroxime Axetil is absorbed
from the gastrointestinal tract and rapidly hydrolyzed by
nonspecific esterases in the intestinal mucosa and blood to
cefuroxime. Cefuroxime is subsequently distributed
throughout the extracellular fluids. The axetil moiety is
metabolized to acetaldehyde and acetic acid.
PHARMACOKINETICS
Comparative Analysis
Side Effect
 There are a number of side effects with cefuroxime axetil that you should
report to your healthcare provider. These include but are not limited to:
 
 Watery or bloody diarrhea (which can occur even after you have finished the
medication)
Seizure
 Signs of an allergic reaction, such as:  
 An unexplained rash
 Hives
 Itching
 Unexplained swelling (especially of the lips, mouth, or throat)
 Wheezing or other breathing problems.
Side Effect
Diarrhea or loose stools -- in up to 10.6 percent of
people
Nausea and vomiting -- up to 6.8 percent
Vaginitis (vaginal inflammation or infection) --
up to 5.4 percent
Dislike of taste (for the oral suspension form) --
up to 5 percent
Diaper rash-- up to 3.4 percent.
Rare Side Effects
These rare cefuroxime axetil side effects included but were not limited
to:

 Abdominal pain (stomach pain) and cramping

 Gas
 Headache
 Chills
 Loss of appetite
 Thirst
 Mouth sores
 Indigestion or heartburn
 Dizziness
 Drowsiness.
Contraindications

Cefuroxime Axetil products are contraindicated in

patients with known allergy to the cepha­losporin
group of antibiotics.
 Chloramphenicol

OH Cl
H
N
Cl
OH Cl
H O
N Esterase O2 N O
Cl H
O
O2 N O
O-Na+ or Water
O OH
O O-Na+
O
O
Chloramphenicol Succinate
Sodium succinate
• Enzymatic and intramolecular spontaneous hydrolysis
• Increased water solubility, ester itself is inactive as an antibiotic
• Promoiety should be nontoxic and easily excreted
• Type of promoiety chosen is a function of properties desired