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2 Seminar on PRODRUGS FOR SITE SPECIFIC DRUG DELIVERY Bharati Vidyapeeth College of Pharmacy, Kolhapur GUIDED BY:- Dr. M. S. BHATIA ( M.phrm Ph.D) PRESENTED BY Mr. Shriram Nikam (M.phrm Sem-1) (Pharm. Chem) 20/11/2010

Abbreviations : 

3 Abbreviations BBB - Blood brain barrier GABA - Gama-aminobutyric acid E.g - Example ADEPT – Antibody directed enzyme prodrug therapy GDEPT – Gene directed enzyme prodrug therapy Ab-E - Antibody enzyme conjugate i.v - Intravenous ASA - Amino salicylic acid GIT- Gastro intestinal tract


4 CONTENTS Introduction Objectives Types Prodrugs For Site Specificity Targeting to Brain Targeting to Kidney Targeting to Colon Targeting to Tumor Conclusion and References


5 INTRODUCTION Prodrug- It is a pharmacologically inactive compound that are converted to an active drug by a metabolic biotransformation. The prodrug can be activated by a non enzymatic process such as hydrolysis. The activation of prodrug may occur at any time during absorption, distribution or metabolism. Prodrug may offer advantage over the active form of drug is being more stable, having better bioavailability, less toxicity and side effect and other desired pharmacokinetic properties.


6 OBJECTIVES To improve membrane permeability. To increase pharmacological activity and sustained release. To minimise toxicity and side effects. To vary water solubility. To improve site specific delivery. To improve chemical stability. To enhance taste.


7 TYPES 1.Carrier linked prodrug- It is a compound that contains an active drug linked with a carrier group that is removed enzymatically. The carrier group must be non- toxic and biologically inactive when detached from drug. The most common reaction for activation of Carrier linked prodrug is hydrolysis.

Mechanism of Carrier linked prodrug : 

8 Mechanism of Carrier linked prodrug

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9 Carrier linked prodrug to improve membrane permeability E.g - Levodopa for Dopamine Dopamine Useful in treating Parkinson’s Disease Too polar to cross cell membranes and BBB Levodopa Lipophilic prodrug and cross cell membrane Carried across cell membranes by carrier proteins for amino acids Decarboxylated in cell to dopamine Levodopa

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10 Prodrug to improve membrane permeability

2.Bioprecursor prodrugs- : 

11 2.Bioprecursor prodrugs- It does not contain a temporary linkage between the active drug & a carrier moiety but designed from a molecular modification of the active principle itself. It is a compound that is converted to active drug by a Metabolic biotransformation. Types of activation- Oxidation (most common method) Reduction Phosphorylation (For antiviral agents)

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12 Oxidation Example – Nabumetone, which is a Non-steroidal anti-inflammatory prodrug used in arthritis

Prodrugs for Site Specificity : 

13 Prodrugs for Site Specificity Site specific delivery is a ultimate goal in all drug delivery research program, where optimal therapeutic benefit of a drug is obtained & unwanted effect are minimized. It is desirable for highly toxic compound such as employed in a cancer. The main aim of Prodrug for Site Specificity is to achieve very precise and direct effect at the target with minimal effect on rest of the body. One important parameter in prodrugs for site specificity is the Drug therapeutic index.

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14 A drug after its absorption into systemic circulation gets distributed into target as well as non-target site. The distribution to non-targeted tissue may leads to undesirable toxic effect and also insufficient concentration to the target site. If the target is too long and take more time for distribution the drug may get eliminated without reaching such a site. To minimize such a problems in a targeted drug delivery prodrug approach has been used. Continued-

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15 Prodrug has been developed in such a manner that they can cross the barriers to get there activity. DRUG BARRIER TO DRUG USEFULNESS DRUG PROMOIETY PROMOIETY DRUG DRUG PROMOIETY NON-TOXIC& EXCRETED RAPIDLY

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16 Novel prodrugs with modified properties has been designed which preferentially achieve higher concentration of biotransformed drug at the desired targeting sites such as- Brain targeting Kidney targeting Liver targeting Virus targeting Tumor targeting Lymphatic targeting Colon targeting


17 TARGETING TO BRAIN In a brain targeting, delivery of drug is limited by Blood Brain Barrier (BBB). The Blood Brain Barrier can allows only small, non-ionic and lipid soluble molecules, which can diffuse the BBB from systemic circulation. But the larger, more water soluble and ionic molecules do not readily cross BBB. The BBB allows only lipophilic molecules to enter brain, on this basis Bodor and Co-workers (1981) developed Dihydropyridine-pyridinium type redox system for Brain specific sustain drug delivery.

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19 As shown in above, the drug containing amine group made lipophilic by coupling with dihydropyridine promoiety that facilitate penetration of prodrug through BBB leading to retention at site. Once prodrug inside the brain the carrier is oxidized into hydrophilic compound to be kept in the brain which slowly hydrolyzed to the drug. E.g- The drug which is used as an anticonvulsant needs to be increasing the concentration of inhibitory neurotransmitter gama-aminobutyric acid (GABA) This increasing the concentration of GABA result in an anticonvulsant activity. Continued-

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20 Example: Progabide GABA is too polar to cross BBB so it is not an effective anticonvulsant drug. Progabide is a lipophilic analog of GABA which cross BBB. Then release GABA inside brain and shows anticonvulsant activity. IN BRAIN

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21 Also zidovudine, Aciclovir, Ganciclovir, etc these are antiviral prodrugs acts by same mechanism.


22 TARGETING TO KIDNEY In kidney targeting there are some possibilities which affect the normal renal distribution of drug- Drug reaching to kidney but they cause unwanted extra renal effect. Drug is inactivated before reaching the site of action in kidney. Abnormalities in pathological conditions such as abnormalities in glomerular filtration, tubular secretion etc. To prevent that possibilities prodrugs are developed for kidney targeting.

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23 Most research on targeted drug delivery to the kidney has focused on development of amino acid prodrugs. Bcoz proximal tubular cell contain high concentration bioconverting enzymes such as L-amino acid decarboxylase, B-lyase, L-glutamyl transpeptidase. Prodrugs are designed to be activated by one or two enzymes in order to release the active parent drug. E.g- Dopamine showed high renal specificity following the intraperitoneal administration of the double prodrug, gama-glutamyl-L-dopa in mice. Continued-

24 gama-glutayml transpeptidase L-DOPA DOPAMINE gama-glutamyl-L-dopa is catalyzed by gama-glutayml transpeptidase to L-dopa L-dopa is decarboxylate to dopamine Dopamine shows desired renal vasodilation effect in kidney Undesirable systemic B.P lowering effect is avoided Level of dopamine in kidney found five times greater than normal dose L-dopa decarboxylate


25 TARGETING TO COLON Drug targeting to colon is achieved by preparing the polar prodrug. There by decreasing the absorption in stomach & intestine within upper GIT. The prodrug is activated by bacterial enzymes presents in colon follows fast absorption through colonic membrane.

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26 E.g – Sulfasalazine Which formed by coupling of diazotized 2-sulfanilamide pyridine with 5-amino salicylic acid (ASA) When administered orally, very limited extent absorbed in upper GIT due to its polar nature. Large percent of intact sulfasalazine reaches to the colon. The azo reductase associated with anaerobic colonic bacteria which converts sulfasalazine to 5- ASA SULFASALAZINE 5-AMINO SALICYLIC ACID


27 TARGETING TO TUMOR Tumor cells contains a higher concentration of enzyme phosphates, amides than do normal cells. Because of higher growth rates associated with tumor cells. For activation prodrug of cytotoxic agents these enzymes are very important. Recent prodrug approach has actively applied to achieve very precise and direct effect at the tumor site of action with minimal effects on rest of body.


28 ENZYME-PRODRUG THERAPIES Incorporate a prodrug-activating enzyme into a target tumor cell. Administer a nontoxic prodrug which is a substrate for the exogenous enzyme incorporated. For tumor drug delivery firstly studied prodrug activating enzyme. For selective activation of prodrugs in tumor cells Two steps:

Criteria for Success With Enzyme-Prodrug Therapies : 

29 Criteria for Success With Enzyme-Prodrug Therapies The prodrug-activating enzyme is either nonhuman or a human protein. It should be a good substrate for the incorporated enzyme but not be activated by endogenous enzyme outside tumor cell. Prodrug must be able to cross tumor cell membranes. Prodrug have low cytotoxicity and drug have high cytotoxicity. The activated drug should be highly diffusable to kill neighboring nonexpressing cells. The half-life of the active drug is long enough for bystander killing effect but short enough to avoid leaking out of tumor cells.

Antibody-Directed Enzyme Prodrug Therapy (ADEPT) : 

30 Antibody-Directed Enzyme Prodrug Therapy (ADEPT) Administration of Antibody-enzyme conjugate Administration of prodrug Prodrug Enzyme Drug Tumor cell An approach for site-specific delivery of cancer drugs

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31 An antibody-enzyme conjugate is administered which binds to the surface of the tumor cells. The antibody used has been targeted for the particular tumor cell. After the antibody-enzyme has localized within the tumor cell and the excess conjugate is cleared from the blood and normal tissues get enough time to clear. After the prodrug is administered, The Ab-E conjugated at the tumor cell surface catalyzes the conversion of the prodrug to the drug when it reaches the tumor cell.

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32 Advantages: Increased selectivity for targeted cell Each enzyme converts many prodrugs to drug molecules The release of drug is at the site of action Demonstrated to be effective at the clinical level Concentrates the drug at the site of action ADEPT Disadvantages: Immunogenicity and rejection of antibody-enzyme conjugate Need i.v. administration. Potential for leakback of the active drug.

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33 Example: Delivery of Nitrogen mustard as a Glutamic acid conjugate, after administration of humanized monoclonal antibody conjugated to the bacterial enzyme carboxypeptidase G2. Prodrug-activating enzyme in ADEPT is a bacterial enzyme. Drawback- Increase immunogenicity and rejection due to use of bacterial enzyme. carboxypeptidase G2 Nitrogen mustard as a Glutamic acid conjugate Activated Nitrogen mustard L-Glu + CO2 +

Gene-Directed Enzyme Prodrug Therapy (GDEPT) : 

34 Gene-Directed Enzyme Prodrug Therapy (GDEPT) An inactive prodrug can be activated to release of cytotoxic drug by an enzyme that has been delivered via gene to the tumor cell. A gene encoding prodrug-activating enzyme is integrated into a genome of targeted tumor cells or viral vector under the control of tumor-selective promoters. These cells, then express the enzyme that activates the prodrug.

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36 (2-nitroimidazole-5-yl) methyl carbamate A common enzyme used for activation of a prodrug by GDEPT is aerobic flavindependent nitroreductase from E. coli B. That catalyses the reduction aromatic nitro groups to the corresponding hydroxylamino group. E.g- (2-nitroimidazole-5-yl) methyl carbamate is a prodrug of amino-seco-CBI-TMI


37 CONCLUSION The prodrug approach has been used to overcome the limitations arising due to various undesirable drug properties to optimize clinical drug applications. Prodrug design is becoming elaborated also in the development of efficient and elective drug delivery systems. Hence prodrugs can be considered as chemical modifications to solve problems associated with pharmacokinetics and site specific delivery of drugs. The targeted prodrug approach intended for site specific action can be combined with gene delivery and controlled expression of enzyme carrier proteins and thus can lead to promising strategy to achieve very precise and direct effect at the site of desired action with minimal effects on rest of the body.


38 REFERENCES N. K. Jain, Advances in Controlled and Novel drug delivery,2005, 268-283. Richard B. Silverman in the Organic Chemistry of Drug Design & Drug Action sec. edition,2004, 497-547. V. M. Kulkarni, K.G. Bothra, in Drug design Nirali prakashan,2006, 15-22. John H. Block, John M. Beale, in Wilson and Gisvold Textbook of organic medicinal chemistry,2004, 142-155. Graham L. Patrick in An introduction to Medicinal chemistry, 2005, 236-242. Prodrug A Sustained Chemical Drug Delivery Approach Pharmainfo_net.htm.

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