1. Prodrugs are pharmacologically inactive compounds that are metabolized into active drug substances within the body. They can improve drug properties like absorption, distribution, metabolism and excretion. 2. Common functional groups used in prodrugs include esters, amides, and Mannich bases, which are metabolized by hydrolysis or other enzymatic reactions. Examples are given of prodrugs that use these functional groups. 3. The goals of prodrugs are to selectively deliver drugs to sites of action, protect drugs from metabolism until they reach target sites, and limit side effects by targeting drug release. Effective prodrugs must be activated rapidly at target sites.

1. Prodrug – Concept & Application Prasented by – Ravindra Kumar Gupta Lecturer , Department of Pharmaceutics BR Nahata College Of Pharmacy , Mandsaur (M.P.)

2. Initial definition : A pharmacologically inactive chemical entity that when metabolized or chemically transformed by a mammalian system is converted into a pharmacologically active substance “ Drug Latentiation ” – included later Process of purposely designing and synthesizing a molecule that specifically requires “bioactivation” to a pharmacologically active substance Why use prodrugs? Improve patient acceptability (decrease pain on injection) Alter and improve absorption Alter biodistribution Alter metabolism Alter elimination Prodrugs

3. “ Hard Drugs ” - compounds that contain structural characteristics required for activity but are not susceptible to metabolism Increased efficiency by avoiding metabolism No toxic metabolites are formed HOWEVER, less readily eliminated due to lack of metabolism “ Soft Drugs ” - These are the opposite of prodrugs. These compounds are designed and synthesized as ACTIVE compounds that readily undergo metabolic inactivation to nontoxic products Non- Prodrugs

4. Conversion of Prodrugs Metabolism (enzyme dependant) Chemical Methods ( non-dependant ) Hydrolysis Decarboxylation NOT patient dependant! Stability/Storage issues

5. Carrier-linked prodrugs – drugs that are attached through a metabolically labile chemical linkage to another molecule designated as the “promoiety” The “promoiety” alters the physical properites of the drug to increase water or fat solubility or provide site-directed delivery Advantages: Increased absorption Injection site pain relief Elimination of unpleasant taste Decreased toxicity Decreased metabolic inactivation Increased chemical stability Prolonged or shortened action Prodrugs

6. Chloramphenicol 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

7. Mutual Prodrug Used for metastatic carcinoma of the prostate Promoiety also a drug! Prodrug is selectively taken up into estrogen receptor positive cells then urethane linkage is hydroylzed 17-alphaestradiol slow prostate cell growth Nornitrogen mustard is a weak alkylating agent

8. Functional Groups in Prodrugs Carboxylic acids and Alcohols: Most common type of prodrug Types of esterase enzymes mediating the hydrolysis process Ester hydrolase, Lipases, Cholesterol esterases, Acetylcholinesterase, Carboxypeptidase, Cholinesterase Bacterial microflora enzymes Wide number of choices of promoiety alcohols available Steric, electronic and hydrophobicity properties allow rate and extent of hydrolysis to be controlled

9. Functional Groups in Prodrugs Erythromycin is a very bitter substance easily destroyed at acidic pH Propionate ester is to increase lipid solubility for improved absorption Ester must be hydrolyzed for antibacterial activity Lauryl sulfate salt – absorption not affected by food, less bitter after taste and is acid stable

10. Esters Failure as Prodrugs

11.  -Lactam prodrug – Double esters Vantin ® – Pharmacia & Upjohn URI, UTI, Gonorrhea, skin infections Taking with food increases absorption Why? Increase absorption Avoid acid catalyzed decomposition

12. Other ester prodrugs - soluble Unstable: use immediately More stable: less prone to hydrolysis by water

13. Amine derivatives as prodrugs Amides not used due to high stability Most common amine derivative used is a Mannich Base prodrug

14. Mannich Base Chemistry Mannich Reaction - This is nucleophilic addition reaction of an aldehyde and at least a secondary amine to produce what is known as a schiff base on protonation and elimination of a water molecule. The Schiff base is often stabilized by resonance. The addition of a carbanaion to the schiff base gives another base called the Mannich base. The Mannich base formed can readily eliminate the secondary amine to give the synthetic usefulness of the reaction, but when primary amines or ammonia are used the hydrogen on nitrogen atom can participate in a further reaction to give more complex products.

15. Azo Prodrugs Bacterial reductases  reductive cleavage Release of 2 amine compounds Occurs in colon  discourages small intestine systemic absorption Concentrates the drug at the desired site of action

16. Carbonyl prodrugs Aldehyde and ketone derivatives Little clinical utility with one exception Methenamine hippurate Hiprex ® - Hoechst Marion Roussel Urex ® - 3M Pharmaceuticals plus a number of combos Used for prophylaxis or suppression/elimination of frequent UTI

17. Bioprecursor Prodrugs Do NOT contain a carrier or promoiety Contain latent functionality Metabolically or chemically transformed into an active drug Types of activation at are predictable Oxidative (most common method) Reductive Phosphorylation (antiviral agents) Oxidation Example – Nabumetone – Relafen ® – Smith Kline Beecham Non-steroidal antiinflammatory Use: Arthritis

18. Reduction example - Mitomycin C - Mutamycin ® - Bristol Myers Adenocarcinoma of the stomach and pancreas Bioprecursor Prodrugs

19. Phosphorylation example – Bioprecursor Prodrugs

20. We have already seen 2 examples of this: Sulfasalazine – an azo compound Methenamine – An urinary antibacterial agent Requirements Prodrug reach the site of action in high concentrations Knowledge of high metabolism at site Other factors Extent of organ or site perfusion Information on the rate of prodrug conversion to the active form at both target and non-target sites Rate of input/output of prodrug from the target site Limit side effects and increase effectiveness Chemical Delivery Systems

21. Types of carriers that have been used Proteins Polysaccharides Liposomes Emulsions Cellular carriers (erythrocytes and leukocytes) Magnetic control targeting Implanted mechanical pumps What is the Basic Goal? Protect a non-specific biological environment from a drug Protect a drug from a non-specific biological environment Especially evaluated for drugs with a narrow therapeutic window especially anti-cancer agents Chemical Delivery Systems

22. The ideal situation: Prodrug readily transported to the site of action Prodrug is rapidly absorbed at the site Selective and rapid conversion to the active drug Kidney and Liver are easy targets due to high perfusion and high metabolic rates Other tissue sites can be problematic for the same reasons Drug migrate slowly (site of action to a site of excretion) Ideal situation is VERY complex to achieve Example : Methenamine the lower the pH, the faster the rate of formaldehyde formed blood pH 7.4 therefore, little formaldehyde formed Chemical Delivery Systems

23. Example : Cancer Chemotherapy Tumor cells have a much higher growth fraction This translates into higher enzymatic activity that can be exploited Target a prodrug to these sites and exploit higher enzyme activity Example : L-Dopa or Levodopa – Anti-Parkinsonism agent Larodopa ® – Roche and Dopar ® - Procter & Gamble Brain has a specific transport system for L-amino acids Dopamine does not cross the blood brain barrier efficiently, is rapidly metabolized by oxidative deamination, and can cause peripheral side effects Chemical Delivery Systems