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 solubilityLow lipophilicityChemical instability
•Pharmacokinetic Properties
Poor distribution across biological membranesGood substrate for first-pass metabolismRapid absorption/excretion when long-term effect DesiredNot 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
Cephalosporins
Carbapenem
Chloramphenicol
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- PivampicillinTalampicillinBacampicillin
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
But a significant difference was found in their mean serum level and cumulative excretion data.
60.9 min for ampicillin
58.4 min for pivampicillin
62.2 min for amoxycillin.
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,
CarbapenemCarbapenems 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
Imipenem+
cilastatin
Panipenem+
betamipron
Meropenem
(1β-methyl group)
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 RelationshipAll 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 designFirst, 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.
ResultsPhysicochemical 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.
CephalosporinsThe
cephalosporins are a class of β- lactum antibiotic originally derived from Acremonium, which was previously known as Cephalosporium".
CefuroximCefuroxime 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-AxetilCefuroxime-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 whenthey are given orally. Higher values are obtained only withcephalosporins that are taken up by carrier systems or whenthe polarity of the carboxylic acid group in the 4 position isreduced by esterification . Esterification of the carboxylicacid group produces derivatives which can be absorbed bypassive diffusion. Therapeutically useful compounds can,
however,be obtained only if the absorbed prodrug ester is readilyconverted back to the active drug. The success of the prodrugester approach depends vitally on the solubility and lipophilicityof the prodrug ester as well as its stability to chemical andenzymatic ester cleavage.
PHARMACOKINETICSAfter 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 EffectDiarrhea 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 EffectsThese rare cefuroxime axetil side effects included but were
not limited to:
Abdominal pain (stomach pain) and cramping Gas HeadacheChills Loss of appetite Thirst Mouth sores Indigestion or heartburnDizziness Drowsiness.
Contraindications
Cefuroxime Axetil products are contraindicated in patients with known allergy to the cepha losporin group of antibiotics.
NH
Cl
OO
O-Na+O
O
ClOH
O2N
NH
Cl
OH
O
ClOH
O2N
O-Na+O
O
OH
Esterase
or Water
Chloramphenicol Succinate
Chloramphenicol
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
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