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Seminar 1 prodrugs
- 2. Prodrugs DR. RUSHIKESH S. KULKARNI(JR1,PHARMACOLOGY)
- 3. Introduction Classification Designing a prodrug Applications Recent advances & future aspects Limitations Conclusion
- 4. Barriers for everything Successful is the one who overcome Drug Target site Pharmaceutical & pharmacokinetic BARRIERS Decrease in Efficacy
- 5. Approaches to increase efficacy Biological Physical Chemical New drug Hard and soft drugs Hard drugs Resistant to biotransformation Increases duration of action Soft drugs Rapid in vivo biotransformation Reduces toxicity Prodrugs
- 6. Biotransformation prior to pharmacological action_ Adrian Albert(1958) “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 possesses improved delivery properties over the parent molecule”
- 8. Methenamine (formaldehyde prodrug) First intentional prodrug 15% of 100 best selling drugs were prodrugs An explosive increase in the use of prodrugs in drug discovery and development Adrien Albert First introduced the term “prodrug”
- 10. • In vivo chemical modification • Oxidative/Reductive activation • New compound active or activation by further metabolism • Prontosil, Cyclophosphamide are converted to their active forms viz. sulphanilamide & phosphoramide mustard by metabolic reduction and cyt p450 in liver respectively AspirinParacetamol Benorylate/Benorilate Sulbactum Ampicillin Sultamicillin TolmetinGlycine •Carrier group is attached via linker to drug •Bacampicillin Bipartite •One carrier(group) •Increased lipophilicity •Hydrolytic activation •Tolmetin-glycine prodrug Tripartite Mutual • Each drug acts as a promoiety for the other agent • Carrier – synergistic drug • Benorylate, Sultamicillin Carrier linked Bioprecursors Prodrugs CarrierDrug Linking structure
- 11. •Enalapril •Slowly deesterified to enalaprilat •Longer duration of action •Less/no first dose hypotension •Potency, no effect of food on absorption •Alphacalcidol •Normally activation of vit d occurs in kidney(1) •Alphacalcidol requires only 3- hydroxylation •Can be effectively used in renal impairments Type IA •@ cellular targets •L-DOPA Type IB •In liver •Enalapril, Alphacalcidol Type IIA • In git • Loperamide oxide, Sulfsalazine Type IIB • In blood • Fosphenytoin Type IIC • Near target • ADEPT, GDEPT Type I(Intracellular) Type II(Extracellular) Based on the site of conversion • Water soluble • Injectionstatus epilapticus • Very less damage to intima • In both saline and glucose
- 13. Improving formulation and administration Enhancing permeability and absorption Changing the distribution profile Protecting from rapid metabolism Increase duration of action Overcoming toxicity problems
- 14. Drug Carrier Target site specifier ADEPT GDEPT Carrier/ Specifier Linker Spacer Simple spacers Multiple release spacers Linker
- 16. Functional groups used for prodrug designing Functional group Esters Carbamates Amides Oximes Prodrug of Carboxyl, Hydroxyl, Thiol Carboxyl, Hydroxyl, Amine Carboxylic acids, Amines Molecules lacking Hydroxyl, Amine or Carboxyl Hydrolysis by Esterases Esterases Carboxypeptidase, Peptidases, Proteases Cytochrome p450 Stability to Hydrolysis Less stable Moderatly stable Most stable No hydrolysis Other remarks Most commonly used prodrug Most often used to increase oral absorption. Targeted drug delivery Strong base Increase membrane permeability & absorption
- 18. Absorption Pharmaceutical applications Pharmacokinetic applications Masking taste & odor Minimizing pain @ injection site Alteration of drug solubility Enhancement of chemical stability Reduction of gi irritation Change of physical form of the drug Enhancement of bioavailability Prevention of pre systemic metabolism Prolongation of duration of action Reduction of toxicity Site specific drug delivery
- 19. By decreasing solubility in saliva Chloramphenicol palmitate Taste By increasing boiling point Diethyl dithio isophthalate(pro drug of ethyl mercaptan) Odor
- 20. By increasing aquous solubility & pH Phosphates and esters of Clindamycin and Phenytoin @ pH 12. Pain Disodium phosphate ester of Betamethasone(1 500*) Acetylated sulfonamide moity added to sodium salt of Parecoxib(300*) Increasing solubility
- 21. By modification of functional group & changing physical properties Bisulfite prodrug of Azacytidine(antineo plastic) Chemical stability By avoiding direct contact, increasing stimulation of acid secretion Decreasing interference with mucous layer Nabumetone(after absorption) 6- MNA G.I. irritation
- 22. Liquid form is unsuitable Liquid drug Solid Prodrug By forming a symmetric molecule having higher tendency to crystalise C2H5SH Ethyl Mercaptan COSC2H5 COSC2H5 1,3-Diester
- 23. Drug Prodrug Propranolol Propranolol hemisuccinate Dopamine L-DOPA Morphine Heroin Passive diffusion (absorption) Bacampicillin Poor solubility in gastric fluids Esters of Erythromycin Lipophilicity By temporary protection of functional group by derivatization Preventing drug – enzyme complex formation by altering physicochemical properties First pass metabolism
- 24. Bambuterol Terbutaline by pseudocholinesterase Slow hydroxylationsingle evening dose Drug(half life) Ester Prodrug(half life) Testosterone(4 hrs) Testosterone propionate(2 days) Estradiol (12 hrs) Estradiol propionate(2-3 days) Fluphenazine (15 hrs) Fluphenazine deacanoate(8 days) By controlling the release rate By controlling rate of conversion of prodrug into active drug. Duration of action Local Nabumetone Local + systemic Ibuterol diisobutyrate ester of Terbutaline(glauco ma) Toxicity
- 26. • Tumor specific monoclonal ab conjugated to drugs • Ab delivers agent to tumor cell • Through receptor mediated pinocytosis Targeting ligand conjugated prodrugsEnzyme activated prodrugs ADEPT GDEPT Ab–drug conjugates Peptide-drug conjugates • Peptide ligands designed to bind with a tumor specific Ag or • Peptide transporter overexpressed in tumor cell Cancer targeting by prodrugs •Ab directed at a tumor associated Ag which localizes the enzyme in the vicinity of tumor •non toxic prodrug (substrate) given iv •Thus conversion only @ tumor site •Gene for foreign enzyme delivered into tumor cells •Non toxic prodrug systemically •Thus conversion only @ tumor site
- 27. Eye •Increasing lipophilicity & solubility •Tight corneal junction •Precorneal drug elimination •Less than 1% drug reach intra ocular tissue Brain •Using dihydropyridine or dihydrotrigonellin e carrier •Dopamine linked to dihydrotrigonellin e •N methyl pyridinium 2 carbaldoxime (2- PAM or Pralidoxime) Liver •Receptors AGP, LDL, HDL, Insulin,EGF, Transferrin •Transporters NCTP, OATs, OCTs •Enzymes Many enzymes, CYP3A4 •Potential for targeting •AGP receptor targeting Ribavarin, MTX, Daunorubicin, Primaquine
- 29. Liposomal prodrug(EE) Drug (EE) Triamcolone 21 palmitate(85%) Triamcolone acetonide(5%) 6 Mercaptopurine – glyceryl monostearate(98%) 6 Mercaptopurine 5 palmitoyl 5 flurouridine(95%) 5 flurouridine(26%) Prodrugs in novel drug delivery systems Use of viral vectors Polymeric prodrugs Liposomes Solid lipid nanoparticles Niosomes Incorporation of prodrug in triglyceride core releases drug slowly. AZT-palmitate ester prodrug Vesicles of “Non ionic surfactant”more stable then phospholipids In phase III (methacraylamide-doxorubicin)
- 30. Emergency situations Liver diseases Unexpected toxic metabolite
- 31. 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