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A seminar on
Prodrugs
BY
K.SUNITHA
M.Pharm. II SEMESTER
DEPARTMENT OF INDUSTRIAL PHARMACY
UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES
KAKATIYA UNIVERSITY
WARANGAL
ANDHRA PRADESH
Contents:
Introduction
Various approaches to enhance efficacy of the drug
Hard and soft drugs
Prodrugs
Classification of prodrugs
Considerations in the design of prodrugs
Strategies in the design of prodrugs
Applications of prodrugs
Prodrug based novel drug delivery approaches
Conclusion
References
BARRIERS TO THE THERAPEUTIC UTILITY OF A DRUG
Pharmaceutical phase
Drug
Pharmacokinetic phase
Manufacture
Release
Dosage form
Drug in sol.
at admin
site
Elimination
Absorption
Drug in various
body
compartments
Distribution
Drug in blood
Elimination
Transport
Pharmacodynamic phase
Elimination
Drug in target
organ
VARIOUS APPROACHES TO ENHANCE THE EFFICACY OF A DRUG:
The therapeutic efficacy can be improved by minimizing or eliminating the
undesirable properties while retaining the desirable ones.
 Biological approach
 Physical approach
 Chemical approach
CHEMICAL MEANS OF OPTIMIZING THE DRUG THERAPEUTICS
1. Design and development of new drugs.
2. Design of hard and soft drugs.
3. Design of prodrugs.
HARD DRUGS
 Resistant to biotransformation.
 Has a long half life.
 Design of hard drug involves metabolic stabilization.
ADVANTAGES:
 Enhanced duration of action
 Less wastage of active moiety
 Avoids generation of potentially active harmful metabolites.
 Limits inter-subject variability
Ex: Conversion of tolbutamide to chlorpropamide.
SOFT DRUGS
A soft drug is a biologically active compound that is biotransformed invivo
in a rapid and predictable manner in to non toxic metabolites.
Design of synthetic soft drug involves introduction of a group or a bond susceptible to
rapid metabolic action.
Ex: natural endogenous compounds such as adrenalin and insulin.
Prodrugs
Prodrugs are pharmacologically inactive derivatives of active drugs that are
designed to maximize the amount of active drug that reaches its site of action, through
manipulation of physicochemical, biopharmaceutical and pharmacokinetic properties of
drug.
They are converted into active drug within the body through enzymatic or nonenzymatic reactions. Also called drug latentiation.
CLASSIFICATION OF PRODRUGS:
1.Carrier linked prodrugs:
Active drug is covalently linked to an inert carrier or transporter moiety.
They have enhanced lipophilicity due to attached carrier. The active drug is
released by hydrolytic cleavage, either chemically or enzymatically.
2.Bioprecursors:
These are inert molecules obtained by chemical modification of the drug
but do not contain a carrier. Such a molecule has the same lipophilicity as the
parent drug and is bioactivated generally by redox biotransformation, only
enzymatically. Ex: NSAID – nabumetone (relafen) - arthritis.
O
CH3
CH3O
Series of oxidative
decarboxylation
OH
CH3O
O
Active form of the drug
that inhibits Prostaglandin
biosynthesis by
cyclooxygenase
3. Mutual prodrugs:
The prodrug comprises of two pharmacologically active agents coupled together to
form a single molecule such that each acts as the carrier for the other.
Ex: Benorylate is mutual prodrug of NSAIDs aspirin and paracetamol.
Ex: Emcyt is a mutual prodrug containing estramustine and nornitrogen mustard
linked to each other.
H3C
OPO3Na2
H3C
OH
Sodium phosphate
and
Carbon dioxide
O
Cl
N
Cl
O
Estermustine Sodium Phosphate
Emcyt® - Pharmacia & Upjohn
HO
Cl
NH
NH+Cl-
Aziridine
Cl
Nornitrogen mustard
Cl
Actual alkylating species
Considerations in the design of prodrugs:
1.
Purpose
2.
Expected properties
3.
Site of transformation
4.
Mechanism of transformation
5.
Chemical half life
Strategies for the design of prodrugs:
1. Carriers:
 Carrier is an inert molecule or the promoiety attached to the active drug moiety
through a metabolically labile linkage.
 The carrier imparts some desirable property to the drug such as increased lipid
or water solubility.
 Carriers that help in directing the active moiety to the target site is called as
specifier.
Specifiers:
Targeting unit part of the prodrug which directs the active moiety to the target site.
 Antibody Directed Enzyme Prodrug Therapy
 Gene Directed Enzyme Prodrug Therapy
 Polymer Directed Enzyme Prodrug Therapy/ Macromolecule Directed Enzyme
Prodrug Therapy
linkers:
A releasable linker or spacer is incorporated between the specifier/carrier and the
parent drug.
Reasons for the application of linkers:
1. Incorporation of appropriate linkage between the promoiety and the active drug.
2. Facilitation of enzymatic action on carrier linked prodrugs.
Classification of linkers:
•
•
Electronic cascade linkers
Cyclization linkers
Doxorubicin attaches β-glucuronide was inert towards clevage by βglucuronidase. When they were linked by a 1,6-elimination linker, the substrate
showed susceptability to the enzyme.
simple spacers:
Multiple release spacers:
functional groups amenable to prodrug design
Prodrug linkage and enzymes involved in the hydrolysis
of linkage:
Prodrug linkage
Hydrolyzing enzymes
Ester
Short and medium chain
Cholinesterases
Aliphatic
Ester hydrolase , Lipase , Cholesterol
Esterase, Acetylcholinesterase ,
Aldehyde oxidase, Carboxypeptidase
Long chain aliphatic carbonate
Pancreatic lipase,Pancreatin,Lipase,
Carboxypeptidase, Cholinesterase
Phosphate, Organic
Acid phosphatase, Alkaline
Phosphatase
Sulfate, organic
Steroid sulfatase
Prodrug Linkage
Hydrolyzing Enzyme
Amide
Amidase
Amino acid
Proteolytic enzymes, Trypsin,
Carboxypeptidase A and B,
Azo
Azo reductase
Carbamate
Carbamidase
Phosphamide
Phosphoramidases
β-Glucuronide
β-Glucuronidase
N-Acetylglucosaminide
α- N-Acetylglucosaminidase
β-Glucoside
β-Glucosidase
APPLICATIONS OF PRODRUGS:
1.Pharmaceutical applications
2.Pharmacokinetic applications
3.Targeted drug delivery
4.Controlled drug delivery
Pharmaceutical applications:
1.Improvement of taste:
 Bitter taste of the drug
 Unsuitable for preparation of suspension.
 Reduce the solubility of the drug in the saliva.
PARENT DRUG
PRODRUG WITH IMPROVED TASTE
chloramphenicol
Palmitate ester
clindamycin
Palmitate ester
sulfisoxazole
Diacetate ester
O
O 2N
CH
CH
CH 2OC
(CH 2)14CH 3
CH3 NH
Lipase
O 2N
CH
CH
CH3 NH
O
CH3
Chloramphenicol palmitate
CH 2 OH
O
CHCl 2
chloramphenicol
2. Improvement of odor:
•The odor of the compound depends upon its vapor pressure.
Ex: ethyl mercaptan is a foul smelling liquid of b.p. 35ᴼC. It is converted into its
phthalate ester, diethyldithio-isophthalate ester which is odorless and has higher
boiling point.
O
C
SC2H5
C
SC2H5
O
Diethyldithio-isophthalate
thioesterase
CH3CH2SH
ethyl mercaptan
3. Change of physical form of the drug:
•Liquid form of the drug unsuitable to formulate as a tablet.
•Conversion of liquid drugs to solid prodrug involves the formation of symmetrical
molecules having a tendency to crystallize.
Ex: 1,3-diester derivative of ethyl mercaptan.
4. Reduction of gastric irritation:
• Increased stimulation of acid secretion.
• Interference with the protective mucosal layer.
parent drug
prodrugs
Salicylic acid
Aspirin
Diethyl stilbestrol
Fosfestrol
Phenyl butazone
N-methyl piperazine salt
Oleandrin
Oleandrine acetate
5. Reduction of pain on injection
• Drug precipitates or penetrates into the surrounding tissues.
• The solution is strongly acidic, alkaline or alcoholic.
Clindamycin-2’-phosphate ester
Phosphatase
Clindamycin HCl
6.Enhancement of solubility and dissolution rate:
 Dissolution is the rate limiting step in the absorption of drug.
 Parenteral and ophthalmic formulations of such agents required.
Parent drug
Prodrugs with enhanced
hydrophilicity
Chloramphenicol
Sodium succinate ester
Tocopherols
Sodium succinate ester
Testosterone
Phosphate ester
Diazepam
L-lysine ester
7. Enhancement of chemical stability:
 Drug must be stable during its shelf-life.
 Penicillins susceptible to hydrolysis and destabilization in acidic pH of stomach.
Parent drug
Prodrugs with enhanced
stability
Azacytidine
Azacytidine bisulfite
carbenicillin
Carindacillin (α-indanol ester)
Carfecillin (α-phenyl ester)
erythromycin
Stearate, ethyl succinate and
estolate prodrugs
Azacytidine bisulfite
pH = 7.4
II. Pharmacokinetic applications:
1. Increasing the bioavailability:
Lipophilic drugs passively absorbed
Reasons:
(a) Lipophilic form of drug has enhanced membrane /water partition coefficient as
compared to hydrophilic form of drug.
Ex: pivampicillin and bacampicillin prodrugs of ampicillin are more lipophilic,
better absorbed (above 98%) and rapidly hydrolyzed to the parent drug in blood.
(b) The lipophilic prodrugs of some drugs have poor solubility in gastric fluids and
thus greater stability and better absorption.
Ex: esters of erythromycin.
Advantage: dose reduction
Ex: Pivampicillin is as effective as Ampicillin
in just one third of the dose of the latter.
2. Prevention of presystemic metabolism
Ester and ether prodrugs of corticosteroids bypass presystemic metabolism.
Ex: triamcolone acetonide
Propronalol has high first pass metabolic effect. Its hemisuccinate ester is resistant
to esterases of liver.
3. Reduction of toxicity:
 NSAIDs cause gastric distress
 Timolol and Epinephrine in the treatment of glaucoma. Lipophilic ester prodrugs
of these drugs have a better intraocular penetration enabling a reduction in dose and
thus adverse effects are minimised.
• the therapeutic index of alkyl ester prodrugs of timolol increased by 16times.
• the therapeutic index of a diester of epinephrine with pivalic acid increased by
10times. The epinephrine prodrug also has increased resistance to oxidation.
4. Prolongation of duration of action:
The two rate controlling steps in the enhancement of duration of action are:
(i) The rate of release of prodrug from the site of application
(ii) The rate of conversion of prodrug into active drug
Ex: i.m. depot injections of lipophilic ester prodrugs of steroids
(testosterone cypionate)
esters of antipsychotics (fluphenazine enanthate and decanoate)
 Bambuterol is a biscarbonate ester prodrug of β2-antagonist terbutaline in
the treatment of asthama. Slowly converted into active form by hydrolysis
by cholineaterases.
 It bypasses presystemic elimination.
 Maximum plasma concentration of terbutaline occurs approxiamately 4-7hrs
after bambuterol administration and efficacy lasts for 24hrs.
 Therefore dose is reduced from thrice a day to once a day.
Requirements for Prodrugs designed for targeted therapy:
1. The tissue associated biomolecule must be present in significantly elevated levels
in that particular tissue compared to normal tissue.
2. Prodrug level must be high enough to generate therapeutic levels of free drug in
the target tissue.
3. Prodrug activation at the other sites must be minimal.
4. Prodrugs must be good substrate or possess high binding affinity for tissue
associated molecule.
5. It must not be rapidly eliminated from the body and must not enter cells randomly.
Strategies for targeting prodrugs
1. Prodrug monotherapy:
These are designed for direct activation or recognition by a tumor/tissue
associated factor.
Is a one-step therapy, only the prodrug is administered.
2. Two step prodrug therapy:
Enzyme which can activate the prodrug is administered in the first step.
In the second step prodrug is administered.
 ADEPT
 GDEPT - VDEPT/BDEPT
 PDEPT/ MDEPT
Assessment of efficiency of drug targeting
Maximum tolerated dose
Therapeutic index (T.I.) =
Minimum effective dose
T.I. of targeted drug
Therapeutic advantage =
T.I. of non-targeted drug
Drug targeting index =
(AUCtarget site/AUCtoxic site )target drug
(AUCtarget site/AUCtoxic site)non-targeted drug
Tumor targeting:
Most chemotherapeutic agents are highly toxic with narrow therapeutic index.
They also effect normal dividing cells.
Undesirable side effects- nausea, vomiting, hair loss, diarrhea, etc.
Development of multi drug resistance by the tumor cells.
Hypoxic cells resistant to radiotherapy.
Irregular blood flow leads to reduced supply of glucose and other nutrients to the
cancer cells, slowing down their rate of division. Thus it becomes difficult to target
these cells with chemotherapeutic agents that kill fast multiplying cells.
Tumor associated factors for targeting:
1. Hypoxia:
The hypoxic condition of tumor tissue is exploited in targeting.
Hypoxia selective cytotoxic agents used in combination therapy with conventional
anticancer chemotherapeutic agents.
Hypoxia selective drugs kill hypoxic tumor cells and other agents kill aerobic tumor
cells.
Ex: N-oxide bioreductive tirapazamine (phase-III clinical trials) is used to treat lung
cancer along with cisplatin.
Tumor associated factors and prodrugs
Protease
Prodrugs
Cathepsin-B
Dipeptides of Daunorubicin,
Paclitaxel, Mitomycin C
Plasmin and u-PA system
Peptide linked Nitrogen mustards
Matrix metalloproteinases
2-L-pyroglutamyl-MTX
Serine protease (prostate specific)
Heptapeptide Dauxorubicin
Receptors
Prodrugs
Folate receptors
Daunorubicin-β melanocyte
stimulating hormone
Hyaluronic acid receptors
Hyaluronic acid-paclitaxel
Asialoglycoprotein receptors
Galactose amine - DOX
Prodrugs for ocular delivery:
 Tight corneal epithelium
 Precorneal drug elimination
 Systemic drug absorption
 Less than 1% of the instilled drug reaches the intra ocular tissue.
 Ocular absorption of drugs can be substantially enhanced by increasing
lipophilicity and solubility of the drug .
Prodrugs for brain targeting:
 BBB is a well-organized dynamic interface that actively and selectively regulates
both the uptake of molecules from the blood into the brain and efflux from the brain
parenchyma back into the systemic circulation.
 Conversion into lipophilic form leads into simultaneous enhancement in transport of
drug to other tissues there by greatly increasing the chance of systemic toxicity.
Dihydropyridine-pyridinium salt redox system:
The drug to be delivered to brain is covalently linked to the lipophilic dihydropyridine
carrier to form a prodrug which partitions across the BBB.
The reduced or the dihydro carrier is oxidized by NAD-NADH system.
Ex: Another inert carrier used to target drugs to brain is dihydro trigonelline. It can be
linked to dopamine and targeted to brain.
Ex: N-methyl pyridinium-2-carbaldoxime (2-PAM or Pralidoxime), a cholineaterase
reactivator.
Prodrugs for liver targeting
Receptors
Asilogycoprotein (AGP), LDL,HDL,
insulin, EGF, transferrin
Transporters
NCTP, OATs, OCTs
enzymes
Many enymes, CYP3A4
Targeting CYP3A4:
Adefovir bispivaloyl oxymethyl prodrug of 9-(2-phosphonylmethoxyethyl)adenine
[PMEA], an antiviral drug. It is activated into active drug by esterases.
Pradefovir is hepdirected prodrug of PMEA.
Asialoglycoprotein receptors:
AGP receptors recognize asialofeutin, asialoorosomucoid, albumin and lipoproteins
that are randomly derivatized with sugar groups and other polymers.
Drugs: Ribavirin, MTX, Dox, Daunorubicin, Primaquine
Recent advances in prodrug targeting:
ADEPT:
Antibody is directed at a tumor-associated antigen to
convey an enzyme to tumor sites and, from a low toxic
prodrug a high toxicity drug would be released by
enzymatic catalysis within tumors.
The active drug would be a small
molecule able to diffuse within a tumor
The free enzyme circulating in the blood is removed by using galactosylated murine
derived antibodies that are recognized and removed by hepatic cells.
Monoclonal
antibody
Trade name
Manufacturer
target
cancer
bevacizumab
Avastin
genentech
VEGF
Colon cancer
Cetuximab
Erbitux
Merck
EGF
Colorectal,
head and neck
Pantitumumab
Vactibix
Amgen
EGF
Colorectal
pertuzumab
omniteag
Gentech
HER2
Breast cancer
Viral vectors:
Adeno virus, adeno associated virus, lenti virus, retrovirus, herpes virus, etc..
Purine nucleotide phosphorylase/fludarabine system in the treatment of prostate
cancer (entered into phase I clinical trails), targeted using Rous sarcoma virus.
Poymeric prodrugs
Prodrugs in novel drug delivery systems:
1.Prodrugs in liposomes:
The triamcolone 21-palmitate showed 85% entrapment efficiency compared to
triamcolone acetonide (5%).
The 6-mercaptopurine showed EE of only 1.5%. When it is linked to glyceryl
monostearate its EE was increased to 98%.
5-Flurouridine (FUR) showed low (26%) EE and rapid leakage during storage (>50%
in 12days). The lipophilic 5’-palmitoyl-5-FUR showed 95% EE and no leakage during
storage.
2. Prodrugs in solid lipid nanoparticles:
Incorporation of prodrug in the triglyceride core releases drug slowly.
Ex: the incorporation of azidothymidine (AZT) in SLN was minimal (<1%) but
the incorporation of AZT-palmitate ester prodrug increased with increasing
phospholipid content to the maximum of 90%.
3. Prodrugs in niosomes:
Niosomes are vesicles of non ionic surfactant.
Chemically more stable than the phospholipids.
Ex: N-(2-hydroxypropyl)methacraylamide –
doxorubicin prodrug showed four-fold increase in
maximum tolerated dose and anti-tumor activity
(phase III).
Conclusion
Recent advances in biotechnology have made it possible to utilize pro-drug
design to develop site specific drug delivery systems which provide various means
of targeting the delivery of parent drugs to specific sites within the body.
Clearly, the increasing demands for more efficacious and less toxic drugs will
ensure that prodrug approaches continue to be exploited in the development of
future drug substances.
References:
•V.J. Stella, R.T. Borchardt, M.J. Hageman, R. Oliyai, H. Maag, J.W. Tilley, Prodrugs:
Challenges and Rewards, Parts 1 and 2 Volume V:
•John H. Block and John M. beale, Jr. ,Wilson and Gisvold’s textbook of Organic
medicinal and Pharmaceutical chemistry, eleventh edition, pg: 142-155.
•Biopharmaceutics and Pharmacokinetics by D.M.Brahmankar and Sunil B.Jaiswal,
pg: 159-176.
•Advances in Controlled and Novel Drug Delivery by N.K.Jain, pg: 269-285.
•Xiaoling Li, Ph.D, Bhaskara R. Jasti, Ph.D,
Design of Controlled Release Drug Delivery
Systems, pg: 75-105.
•Binghe Wang, terune Siahaan, and Richard A.
Soltero’s Drug delivery principles and
applications
•Review article on Exploitation of Bile Acid Transport Systems in Prodrug Design by
Elina Sievanen University of Jyvaskyla, Department of Chemistry,University of
Jyvaskyla, Finland 14 August 2007 / Published: 16 August 2007