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Prodrugs an approach to solve problems related to adme

prodrugs an approach to overcome problems related to ADME, for MPharm students
sub- modern pharmaceutical and medicinal chemistry
branch- quality assurance

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Prodrugs an approach to solve problems related to adme

  1. 1. Presenter : Ms. Jyotsna G. Patil M.Pharmacy (Quality Assurance) 1st semester Guided by: Mrs. Malathi Raghunath GAHLOT INSTITUTE OF PHARMACY
  2. 2. What are PRODRUGS  The term ‘Prodrug’ describes compounds which undergo biotransformation prior to exhibiting their pharmacological effects.  Prodrugs are pharmacologically inactive chemical derivatives of a drug molecule that require a transformation (enzymatic or nonenzymatic) within the body in order to release the active drug.  Goal: improve ADME/Tox- or physicochemical properties  Prodrug is successfully studied to target the drug specifically to site of action for better therapy.
  3. 3. An illustration of the prodrug concept (Huttunen et al., 2011)
  4. 4. Objectives of prodrug design  Pharmaceutical objective - improved solubility (chloramphenicol succinate ester) - improved chemical stability (propranolol hemisuccinate ester) - improved taste, odour (clindamycin palmitate) - decreased irritation & pain (sulindac, clindamycin phosphate)  pharmacokinetic objectives - improved absorption (carbecillin, geocillin) - decreased presystemic metabolism (acetonide of triamcinolone) - improved absorption by non-oral routes (amino acid ester approach) - improved prolong duration of action (fluphenazine ester prodrugs)  pharmacodynamic objectives - masking of reactive agent to improve its therapeutic index - in situ activation of a cytotoxic agent (tirapazamine)
  5. 5. ADME  ADME is an abbreviation in pharmacokinetics and pharmacology for “ Absorption, Distribution, Metabolism and Excretion.”  It describes the disposition of pharmaceutical compound within an organism.  Absorption (bioavailability)  Distribution (lower plasma concentration)  Metabolism (metabolites- active/inactive)  Excretion (termination of drug’s action)
  6. 6. Problems associated with ADME  Incomplete absorption  Too rapid or too slow transport of the drugs to the body  Incomplete systemic delivery of an agent  Toxicity problems  Poor site specificity
  7. 7. USE OF PRODRUGS TO OVERCOME PHARMACOKINETIC BARRIERS ABSORPTION PROBLEMS Poor absorption due to: 1. High water solubility 2. Limited water solubility eg. cardiac glycoside such as gitoxin.
  8. 8. Enhancement of Oral Absorption Drug To improve absorption Water soluble vitamins derivatization of thiolate ion to form lipid soluble prodrugs dopamine L-Dopa (active transport mechanism) ampicillin acyloxymethyl ester (bacampicillin, talampicillin and pivampicillin carbenicillin α-carboxy ester (carbecillin, geocillin) Gitoxin (water insoluble) penta acetyl prodrug
  9. 9. Prodrugs used in enhanced oral absorption ampicillin 8.44 O N NH2 NH O S COO- esterase bacampicillin (R = CH3, R' = OEt) pivampicillin (R = H, R' = t-Bu) 8.45 8.46 .. + R'COOH when R' = OEt EtOH + CO2 8.44 NH2 N S NH O Ph O O O O R R' O NH2 N S NH O Ph O O O R R H O OH 1)Ampicillin prodrugs
  10. 10. 2)Dopamine prodrug  Dopamine is water soluble  Levodopa is rapidly absorbed from the small intestine.
  11. 11. Enhancement of Ophthalmic Absorption  The usefulness of epinephrine as adrenergic agent in the treatment of glaucoma is limited due to its highly polar nature.  Dipivalyl derivative of epinephrine formed by the acylation of phenolic hydroxyl groups showed enhanced therapeutic effectiveness.  Lipid solubility of Dipivalyl derivatives is far superior to its parent compound, which facilitates its transport through a lipoidal barrier during corneal absorption.  Dipivalyl Epinephrine: A New Pro-Drug in the Treatment of Glaucoma
  12. 12. Enhancement of Percutaneous Absorption  Mefenide and corticosteroid  The problem of poor percutaneous absorption of corticosteroid was overcome by making various ester prodrugs.  Mefenide and corticosteroid are used in the treatment of inflammatory, burn therapy, allergic and pruritic conditions, but have limited application due to poor percutaneous absorption.
  13. 13. Prevention of pre-systemic metabolism  Presystemic metabolism of drug is due to - Phenolic moiety - Oxidative N– and O– dealkylation - Ester cleavage - Peptide degradation  Two types of drug - rapidly degraded by the acid condition of the stomach - degrade due to enzymes present in the gastrointestinal mucosa and liver
  14. 14. Prevention of pre-systemic metabolism  The first pass metabolism of a drug can be prevented if the functional group susceptible to metabolism is protected temporarily by derivatization.  The prodrug approach was successfully used to overcome the problem of considerable metabolism of steroid drugs, propranolol, dopamine, morphine and catecholamines
  15. 15. Prevention of pre-systemic metabolism DRUG PRODRUG APPROACH Steroids Acetylated derivatives Corticosteroids 17α, 21-acetonides Propranolol Hemisuccinate ester Dopamine L-Dopa Morphine Diacetyl prodrug
  16. 16. Morphine prodrug  Morphine is subject to extensive first-pass metabolism (a large proportion is broken down in the liver), so, if taken orally, only 40–50% of the dose reaches the central nervous system.  When someone takes heroin, either by means of injection, smoking, the drug enters the bloodstream, then travels towards the brain, hits the blood-brain barrier, already having been converted to 6-mono-acetylmorphine (6MAM) through hydrolysis. This compound, unlike pure morphine, is lipid-soluble and races through into the brain with almost no delay. Then the 6MAM rapidly breaks down into morphine.
  17. 17. Morphine prodrug Morphine Heroin
  18. 18. Corticosteroid prodrug  Several corticosteroids undergo extensive first-pass hepatic metabolism which can be prevented by use of their ester or ether prodrugs.
  19. 19. Longer duration of action  Prolongation of duration of action of a drug can be accomplished by the prodrug approach and can take two forms.  First the input of drug in to the body can be controlled by a prodrug/drug delivery formulation complex, which by design releases drug at a controlled rate at the absorption site, followed by conversion to drug prior to or just after absorption.  Second a prodrug can be designed wherein the conversion to the parent drug becomes the release rate limiting factor in the systemic milieu.
  20. 20.  This approach is most useful in case of neuroleptic drugs to avoid large fluctuation in plasma levels.  This could be successfully achieved by administering heptanoate and decanoate esters of fluphenazine in sterile sesame oil. Fluphenazine prodrug  Fluphenazine is a short acting piperazine phenothiazine.  Onset of action: within 1 hr.  Duration of action: 6 to 8 hr.  Reported half life: 13 to 33 hr. or more
  21. 21. Cont...  Fluphenazine esters in sesame oil slows their release resulting in longer duration of action.  Onset of action: 24 to 72 hr.  Avg. duration of action: 2 to 3 weeks.
  22. 22. To Diminish Local and Systemic Toxicity of Drugs  Therapeutic activity without toxicity  Very difficult unless site specific delivery of drug is achieved  Various non steroidal anti inflammatory drugs like salicylic acid and indomethacin severely damage the GI mucosa due to presence of free carboxylic group.
  23. 23. Cont…  Few other therapeutic agents such as sulindac sulfide, 5, 5-ethyl phenylhydrazine and phenytoin, and antibiotic such as adriamycin suffer with the problem of toxicity due to inadequate aqueous solubility, improper distribution and high tissue distribution respectively

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prodrugs an approach to overcome problems related to ADME, for MPharm students sub- modern pharmaceutical and medicinal chemistry branch- quality assurance


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