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Prodrug strategy

Prodrug strategy

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Prodrug strategy

  1. 1. Prodrug Strategy (Concept & Applications) Presented By: Anvita Jadhav M.Pharm(Pharmaceutics) 1
  2. 2. Prodrug concept • The concept of “prodrug” was first introduced by Adrian Albert in 1958 to describe compounds that undergo biotransformation prior to eliciting their pharmacological effect. • A prodrug is defined as a biologically inactive derivative of a parent drug molecule that usually requires a chemical or enzymatic transformation within the body to release the active drug, and possess improved delivery properties over the parent molecule. • The development of prodrugs is now well established as a strategy to improve the physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically potent compounds, and thereby increase usefulness of a potential drug. 2
  3. 3. Schematic illustration of the prodrug concept Extracellular Fluid Site of Action (cell or cell surface) Pharmacokinetic or Physicochemical barrier 3
  4. 4. History and the Present of Prodrug Design 1899 Methenamine First intentional Prodrug 1935 Protonsil Antibiotic 1958 Adrien Albert First introduced the term “pro-drug” 1960 An explosive increase in the use of prodrugs in drug discovery and development. 2009 15% of the 100 best selling drugs were Prodrugs 4
  5. 5. Rationale for prodrug design A. Improving formulation and administration B. Enhancing permeability and absorption C. Changing the distribution profile D. Protecting from rapid metabolism E. Overcoming toxicity problems 5
  6. 6. Properties of ideal prodrug 1. • Pharmacological Inertness 2. • Rapid transformation, chemically or enzymatically, into the active form at the target site 3. • Non-toxic metabolic fragments followed by their rapid elimination 6
  7. 7. Classification of Prodrugs Prodrugs Carrier linked prodrug Bipartite prodrug Tripartite prodrug Mutual Prodrugs Bioprecursors 7
  8. 8. Active Drug Inert Carrier A) Carrier linked prodrug Chemical Prodrug Formation Chemical/Enzymatic cleavage in vivo Covalent Bond  Carrier linked prodrug consists of the attachment of a carrier group to the active drug to alter its physicochemical properties.  The subsequent enzymatic or non-enzymatic mechanism releases the active drug moiety. 8
  9. 9. 1. Bipartite prodrug • It is composed of one carrier (group) attached to the drugs. • Such prodrugs have greatly modified lipophilicity due to the attached carrier. The active drug is released by hydrolytic cleavage either chemically or enzymatically. • E.g. Tolmetin-glycine prodrug. It can be further subdivided into TolmetinGlycine 9
  10. 10. 2. Tripartite prodrug- Drug Linking Structure Carrier The carrier group is attached via linker to drug. 10
  11. 11. 3. Mutual Prodrugs • A mutual prodrug consists of two pharmacologically active agents coupled together so that each acts as a promoiety for the other agent and vice versa. • A mutual prodrug is a bipartite or tripartite prodrug in which the carrier is a synergistic drug with the drug to which it is linked. • Benorylate is a mutual prodrug aspirin and paracetamol. • Sultamicillin, which on hydrolysis by an esterase produces ampicillin & sulbactum. 11
  12. 12. AspirinParacetamol Sulbactum Ampicillin Benorylate/Benorilate Sultamicillin 12
  13. 13. B) Bioprecursors • Bio- precursor prodrugs produce their effects after in vivo chemical modification of their inactive form. • Bioprecursor prodrugs rely on oxidative or reductive activation reactions unlike the hydrolytic activation of carrier-linked prodrugs. • They metabolized into a new compound that may itself be active or further metabolized to an active metabolite 13
  14. 14. Classification based on the site of conversion Type I – Metabolized Intracellularly Type IA prodrugs Metabolized at the cellular targets of their therapeutic actions E.g., acyclovir, cyclophosphamide, L- DOPA, zidovudine Type IB prodrugs It converts into parent drugs by metabolic tissues, namely by the liver E.g., carbamazepine, captopril, heroin, primidone 14
  15. 15. Type II – Metabolized Extracellularly Type IIA In the milieu of gastrointestinal fluid E.g., loperamide oxide, sulfsalazine, Type IIB Within the circulatory system and/or other extracellular fluid compartments E.g., aspirin, fosphenytoin Type IIC Near therapeutic target/cells E.g. ADEPT, GDEPT 15
  16. 16. 1. Esters as prodrugs of carboxyl, hydroxyl and thiol functionalities • Esters are the most common prodrugs used, and it is estimated that approximately 49% of all marketed prodrugs are activated by enzymatic hydrolysis. • Ester prodrugs are most often used to enhance the lipophilicity, and thus the passive membrane permeability, of water soluble drugs by masking charged groups such as carboxylic acids and phosphates. • The synthesis of an ester prodrug is often straightforward. Once in the body, the ester bond is readily hydrolysed by ubiquitous esterases found in the blood, liver and other organs and tissues, including carboxyl esterases, acetylcholinesterases, butyrylcholinesterases, paraoxonases and arylesterases. Functional Groups Amenable to Prodrug Design 16
  17. 17. 2. Carbonates and carbamates as prodrugs of carboxyl, hydroxyl or amine functionalities: • Carbonates and carbamates differ from esters by the presence of an oxygen or nitrogen on both sides of the carbonyl carbon. • They are often enzymatically more stable than the corresponding esters but are more susceptible to hydrolysis than amides. • Carbonates are derivatives of carboxylic acids and alcohols, and carbamates are carboxylic acid and amine derivatives. • The bioconversion of many carbonate and carbamate prodrugs requires esterases for the formation of the parent drug. 17
  18. 18. 3. Amides as prodrugs of carboxylic acids and amines • Amides are derivatives of amine and carboxyl functionalities of a molecule. In prodrug design, amides have been used only to a limited extent owing to their relatively high enzymatic stability in vivo. • An amide bond is usually hydrolyzed by ubiquitous carboxylesterases, peptidases or proteases. Amides are often designed for enhanced oral absorption. • Lipophilicity of various compounds like acid chlorides and acids can be altered in many groups of compounds by amide formation. • This approach is successful to improve the stability of drug in vivo in many of the pharmaceutical agents and gives targeted drug delivery due to presence of enzyme amydase. 18
  19. 19. 4. Oximes as derivatives of ketones, amidines and guanidines • Oximes (for example, ketoximes, amidoximes and guanidoximes) are derivatives of ketones, amidines and guanidines, thus providing an opportunity to modify molecules that lack hydroxyl, amine or carboxyl functionalities. • Oximes are hydrolyzed by the versatile microsomal cytochrome P450 (CYP450) enzymes. • Oximes, especially strongly basic amidines and guanidoximes, can be used to enhance the membrane permeability and absorption of a parent drug. 19
  20. 20. Applications of prodrugs Pharmaceutical Applications Masking Taste & Odor Minimizing Pain at Site of Injection Alteration of Drug Solubility Enhancement of Chemical Stability Reduction of G.I. irritation Change of physical form of the drug Pharmacokinetic Applications Enhancement of bioavailability (Lipophilicity) Prevention of Pre-systemic Metabolism Prolongation of duration of action Reduction of toxicity Site specific drug delivery 20
  21. 21. Masking Taste & Odor Taste Masking: • The undesirable taste arises due to adequate solubility and interaction of drug with taste receptors, which can be solved by lowering the solubility of drug or prodrug in saliva. • Chloramphenicol, an extremely bitter drug has been derivatized to chloramphenicol palmitate, a sparingly soluble ester. • It possesses low aqueous solubility which makes it tasteless and later undergoes in vivo hydrolysis to active chloramphenicol by the action of pancreatic lipase. Odor Masking: • The ethyl mercaptan (tuberculostatic agent)has a boiling point of 25ºC and a strong disagreeable odour. • Diethyl dithio isophthalate, a prodrug of ethyl mercaptan has a higher boiling point and is relatively odourless. Pharmaceutical Applications 21
  22. 22. Minimizing Pain at Site of Injection • Pain caused by intramuscular injection is mainly due to the weakly acidic nature or poor aqueous solubility of drugs. • Example, intramuscular injection of antibiotic like clindamycin and anticonvulsant drug like phenytoin was found painful due to poor aqueous solubility and could be overcome by making phosphate ester prodrugs respectively and maintaining the formulations at pH 12. 22
  23. 23. Alteration of Drug Solubility • The prodrug approach can be used to increase or decrease the solubility of a drug, depending on its ultimate use. Example- • The solubility of betamethasone in water is 58 μg/ml at 25⁰C. The solubility of its disodium phosphate ester (a charged ester promoeity) is more than 100 mg/ml, an increase in water solubility greater than 1500-fold. • Acetylated sulfonamide moiety enhanced the aqueous solubility of the poorly water-soluble sodium salt of the COX-2 inhibitor Parecoxib ~300-fold. 23
  24. 24. Enhancement of Chemical Stability • Although chemical unstability can be solved to a greater extent by appropriate formulations, its failure necessitates the use of prodrug approach. The prodrug approach is based on 1. modification of the functional group responsible for the instability or 2. by changing the physical properties of the drug resulting in the reduction of contact between the drug and the media in which it is unstable. • E. g. Antineoplastic drug- Azacytidine. • The aqueous solution of azacytidine is readily hydrolyzed but the bisulfite prodrug shows stability to such degradation at acidic pH and is also more water soluble than the parent drug. • The prodrug gets converted to active drug at the physiological pH 24
  25. 25. Reduction of G.I. irritation • Several drugs cause irritation and damage to the gastric mucosa through direct contact, increased stimulation of acid secretion or through interference with protective mucosal layer. Drug Prodrug Salicylic acid Salsalate, Aspirin Diethyl stilbestrol Fosfestrol Kanamycin Kanamycin pamoate Phenylbutazone N-methyl piperazine salt Nicotinic acid Nicotinic acid hydrazide 25
  26. 26. Change of physical form of the drug • Some drugs which are in liquid form are unsuitable for formulation as a tablet especially if their dose is high. • The method of converting such a liquid drug into solid prodrug involves formation of symmetrical molecules having a higher tendency to crystallize e.g. ester of Ethyl mercaptan and trichloro ethanol. 26
  27. 27. Enhancement of bioavailability (Lipophilicity) • Passive diffusion is the commonest pathway for transportation of drug from site of administration to systemic circulation through a lipoidal membrane. • Thus improvement in the lipophilic character serves as a tool for betterment of bioavailability. Two reasons can be attributed to the enhanced oral bioavailability of lipophilic compound - a) The lipophilic form of a drug has enhanced membrane /water partition coefficient as compared to the hydrophilic form thus favoring passive diffusion e.g. Bacampicillin prodrugs of Ampicillin is more lipophilic, better absorbed and rapidly hydrolyzed to the parent drug in blood. b) The lipophilic prodrugs have poor solubility in gastric fluids and thus greater stability and absorption e.g. ester of Erythromycin. Pharmacokinetic Applications 27
  28. 28. 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. • Alternatively manipulation of the drug to alter its physicochemical properties may also alter the drug – enzyme complex formation. Drug Prodrug Propranolol Propranolol hemisuccinate Dopamine L-DOPA Morphine Heroin 28
  29. 29. Prolongation of duration of action • Drugs with short half life require frequent dosing with conventional dosage forms to maintain adequate plasma concentration of the particular drug. • In plasma level time profile and consequently patient compliance is often poor. • Prolongation of duration of action of a drug can be accomplished by the prodrug . Prodrug can be formed by two approaches- Drug Ester Prodrug Testosterone Testosterone propionate Estradiol Estradiol propionate Fluphenazine Fluphenazine deaconate 1. To control the release rate of prodrug. 29
  30. 30. 2. To control the rate of conversion of prodrug into active drug in the blood. • This second approach of controlled conversion of prodrug to active drug was difficult, it was successfully utilized to deliver Pilocarpine to eyes in the treatment of glaucoma. • The diesters of drug when applied as ophthalmic solution showed better intra-ocular penetration due to improved lipophilicity and slow conversion of the ester prodrug to active Pilocarpine resulted into prolonged the therapeutic effect 30
  31. 31. Reduction of toxicity • An important objective of drug design is to develop a moiety with high activity and low toxicity • NSAIDs local side effects like gastric distress with various, which can be overcome by prodrug design. • Another example is the bioprecursor Sulindac, as it is a sulphoxide, it doesn’t cause any gastric irritation and also better absorbed. • The prodrug Ibuterol is diisobutyrate ester of Terbutaline (a selective β-agonist useful) in glaucoma. This prodrug, is 100 times more potent, has longer duration of action and is free from both local and systemic toxicity. 31
  32. 32. Site specific drug delivery • After its absorption into the systemic circulation, the drug is distributed to the various parts of the body including the target site as well as the non-target tissue. • These problems can be overcome by targeting the drug specifically to its site of action by prodrug design • The prodrug is converted into its active form only in the target organ/tissue by utilizing either specific enzymes or a pH value different from the normal pH for activation e.g. 5-amino salicylic acid. 32
  33. 33. Site specific drug delivery for cancer • As oncostatic drugs are endowed with poor selectivity. The lack of selectivity of anticancer drugs, and associated toxicity, hampers their effectiveness and long term use. Hence, not surprisingly, there is an urgent need to improve their selectivity. • prodrug technology can be used to site specific delivery of anticancer drugs. • Anticancer prodrugs can be designed to target specific molecules (enzymes, peptide transporters, antigens) that are overexpressed in tumor cells in comparison to normal cells. The new promising chemotherapeutic prodrugs include: 1. Enzyme-activated prodrugs • ADEPT • GDEPT 2. Targeting-ligand conjugated prodrugs • Antibody-drug conjugates • Peptide-drug conjugates 33
  34. 34. 1. Enzyme-activated prodrugs • One approach toward improving the specificity of chemotherapy is enzyme-activated prodrug therapy in which a non-toxic drug is converted into a cytotoxic agents, i.e. antimetabolites and alkylating agents. • E.g. ADEPT, GDEPT 34
  35. 35. Antibody-directed enzyme prodrug therapy (ADEPT) • The principle of ADEPT is to use an antibody directed at a tumor-associated antigen which localizes the enzyme in the vicinity of the tumor. • A non-toxic prodrug, a substrate for the enzyme, is then given intravenously and converted to a cytotoxic drug only at the tumor site where the enzyme is localized, resulting in tumor cell death. Antibody Prodrug Drug Tumor target L6 Mitomycin C phosphate Mitomycin C Lung adenocarcinoma BW413 Etoposide phosphate Etoposide Colon carcinoma L6 Doxorubicin phosphate Doxorubicin Lung adenocarcinoma 35
  36. 36. Schematic presentation of antibody-directed enzyme prodrug therapy (ADEPT). mAb-enzyme conjugate is given first, which binds to antigens expressed on tumor surfaces. Prodrug is given next, which is converted to active drug by the pre-targeted enzyme. 36
  37. 37. Gene-directed enzyme prodrug therapy - GDEPT • GDEPT, is a two-step process. In the first step, the gene for a foreign enzyme is delivered to tumor cells. In the second step, a non-toxic agent is administered systematically and converted by the enzyme to its cytotoxic metabolite. Enzyme Prodrug Drug Cytochrome p450 Cyclophosphamide, ifosfamide Phosphamide mustard, acrolein Cytosine deaminase 5-Fluorocytosine 5-Fluorouridine 5-Fluorouracyl Nitroreductase 5-(Aziridin-1-yl)-2,4- dinitrobenzamide 5-(Aziridin-1-yl)-4- hydroxylamino-2- nitrobenzamide 37
  38. 38. Schematic presentation of gene-directed enzyme prodrug therapy (GDEPT). Gene for foreign enzyme is transfected to tumor cells, which express the enzyme to activate the systemically administered prodrug 38
  39. 39. 2. Targeting-ligand conjugated prodrugs • Antibody-drug conjugates: • Tumor-specific monoclonal antibodies (or fragments of antibodies) are conjugated to oncostatic drugs such as antifolates, anthracyclines, taxanes and vinca alkaloids. • The antibody delivers the therapeutic agent to tumor cells. After reaching its target, the conjugate is internalized through a receptor- mediated pinocytosis, and the pharmacologically active compound is released in the cell. • Peptide-drug conjugates: • Peptide-conjugated prodrugs for cancer therapy utilize peptide ligands designed to bind with a tumor specific antigen or a peptide transporter which is overexpressed in neoplastic cells. • These ligands are conjugated to a chemotherapic agent either directly or by a linker. 39
  40. 40. Marketed Prodrugs Fosphenytoin Fenofibrate Rabeprazole 40
  41. 41. Limitations of Prodrug Design • Formation of unexpected metabolite from the total prodrug that may be toxic. • The inert carrier generated following cleavage of prodrug may also transform into a toxic metabolite. • During its activation stage, the prodrug might consume a vital cell constituent leading to its depletion. 41
  42. 42. CONCLUSION Prodrug design is a part of the general drug discovery process, in which a unique combination of therapeutically active substances is observed to have desirable pharmacological effects. In human therapy prodrug designing has given successful results in overcoming undesirable properties like absorption, nonspecificity, and poor bioavailability and GI toxicity. Thus, prodrug approach offers a wide range of options in drug design and delivery for improving the clinical and therapeutic effectiveness of drug. 42
  43. 43. References: • Patil S.J., P.J. Shirote, Prodrug Approach: An Effective Solution to Overcome Side-effects, International Journal of Medical and Pharmaceutical Sciences, Vol 1, Issue 7, Pg. No. 1-13, 2011. • Jolanta B. Zawilska, Jakub Wojcieszak, Agnieszka B. Olejniczak, Prodrugs: A Challenge for the Drug Development, Pharmacological Reports, 65, Pg. No. 1-14, 2013. • Arik Dahan, Ellen M. Zimmermann and Shimon Ben-Shabat, Modern Prodrug Design for Targeted Oral Drug Delivery, Molecules, 19, Pg. No. 16489-16505, 2014. • Jarkko Rautio, Hanna Kumpulainen, Tycho Heimbach, Reza Oliyai§, Dooman Oh|, Tomi Järvinen and Jouko Savolainen, Prodrugs: design and clinical applications, Nature Reviews: Drug Discovery, Vol.7, Pg. No.255-270, March 2008. • Longqin Hu, The prodrug approach to better targeting,Pg. No. 28-32 August 2004. • V.S. Tegeli, Y.S. Thorat, G.K. Chougule, U.S. Shivsharan, G.B. Gajeli, S.T. Kumbhar, Concepts and Advances In Prodrug Technology, International Journal of Drug Formulation & Research, Vol. 1(iii), Pg.No. 32-57, Nov.-Dec. 2010. 43
  44. 44. • V. Stell, Pro-drugs: An Overview and Definition, PRO-DRUGS, Pg. No. 1-115, 1975. • Kuei-Meng Wu, A New Classification of Prodrugs: Regulatory Perspectives, Pharmaceuticals, 2, Pg. No. 77-81, 2009. • Supriya Shirke, Sheetal Shewale and Manik Satpute, Prodrug Design: An Overview, International Journal of Pharmaceutical, Chemical and Biological Sciences, 5(1), Pg. No. 232- 241, 2015. • Kristiina M. Huttunen, Hannu Raunio, and Jarkko Rautio, Prodrugs—from Serendipity to Rational Design, Pharmacological Reviews, Vol. 63, No. 3, Pg. No. 750–771, 2011. • Yashveer Singh, Matthew Palombo, and Patrick J. Sinko, Recent Trends in Targeted Anticancer Prodrug and Conjugate Design, Curr Med Chem, 15(18), Pg. No. 1802–1826, 2008. • Hanna Kumpulainen, Novel Prodrug Structures for Improved Drug Delivery, Pg. No. 15-131, 2007. • Sunil S. Jambhekar, Chapter 3 Physicochemical and Biopharmaceutical Properties of Drug Substances and Pharmacokinetics, Foye’s Principles of Medicinal Chemistry, 7th Edition, Pg. 74-76, 2013. • D. M. Brahmankar and Sunil B. Jaiswal, Biopharmaceutics and Pharmacokinetics – A Treatise, Chapter 6 Prodrugs, 159 – 177, 1995. 44
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