PRODRUG APPROACHES FORCNS DRUG DELIVERYReview Article By : Jarkko Rautio, Krista Laine, Mikko           Gynther, And Jouko...
CONTENTSI.    IntroductionII.   Prodrug ConceptIII.  Role of Increased Lipophilicity In CNS      Drug DeliveryIV. Endogeno...
INTRODUCTION   Blood Brain Barrier(BBB):- Structural and functional barrier    for the delivery of therapeutic agents to ...
Fig. 1 : Chemistry and biology based approaches toincrease brain delivery of CNS targeted therapeutic agents
   For a drug to readily cross the BBB by passive diffusion – less    molecular weight , lipid soluble, neutral and capab...
PRODRUG CONCEPTThe term Prodrug or proagent – Introduced in 1958 – Described asbioreversible derivatives of drug molecules...
   The major goal in Prodrug design is to overcome the various    physicochemical, pharmaceutical, biopharmaceutical, and...
ROLE OF INCREASEDLIPOPHILICITY IN CNS DRUG        DELIVERY   A frequent challenge with new drug candidates, in regard to ...
   Lipidization Approach :•        With increased lipophilicity, for example through simple     ester prodrugs, increased...
The role of BBB efflux transporters in lipophilic prodrug CNS entry
•      The figure illustrates the challenge when the parent drug is a    substrate for an efflux transporter at the BBB. I...
Chemical Drug Delivery Systems :•       A successful prodrug approach that utilizes improved    lipophilicity and also req...
ENDOGENOUS       TRANSPORTERS IN CNS        PRODRUG DELIVERY   The BBB expresses several different transport mechanisms t...
   Carrier-mediated Transport:•      Several specific endogenous influx transporters have been    identified at the BBB f...
   Large neutral amino acid transporter:- This transport system is    expressed on the luminal and abluminal membranes of...
OVERCOMING EFFLUX            TRANSPORT   Transport out of the brain also plays a critical role in efficient    drug deliv...
• Co drug approach explored to improve L-dopa brain delivery with apotent inhibitor entacapone, as a form of L-dopa-entaca...
ANTIBODY AND GENE-         DIRECTED PRODRUG             THERAPIES•   More selective prodrug activation in targeted tissues...
CONCLUSIONS   Recent advances in biotechnology and pharmaceutical sciences have    greatly expanded the number of drugs t...
REFERENCES   W.M. Pardrige. Why is the global CNS Pharmaceutical Market so    under-penetrated. Drug Discov. Today. 7(1):...
REFERENCES (Contd.)   C.H. Lai, and K.H. Kuo. The critical component to establish in vitro    BBB model: Pericyte. Brain ...
Prodrug approaches for cns delivery ppt finished copy
Prodrug approaches for cns delivery ppt finished copy
Prodrug approaches for cns delivery ppt finished copy
Prodrug approaches for cns delivery ppt finished copy
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Prodrug approaches for cns delivery ppt finished copy

  1. 1. PRODRUG APPROACHES FORCNS DRUG DELIVERYReview Article By : Jarkko Rautio, Krista Laine, Mikko Gynther, And Jouko Savolainen Published In The AAPS Journal, Vol. 10, No. 1, March 2008 Seminar Presented by Atulkumar Thakur 1st Year M.Pharm Department of Pharmaceutics MSRCP
  2. 2. CONTENTSI. IntroductionII. Prodrug ConceptIII. Role of Increased Lipophilicity In CNS Drug DeliveryIV. Endogenous Transporters In CNS Prodrug DeliveryV. Overcoming Efflux TransportVI. Antibody And Gene-Directed Prodrug TherapiesVII. ConclusionsVIII. References
  3. 3. INTRODUCTION Blood Brain Barrier(BBB):- Structural and functional barrier for the delivery of therapeutic agents to the CNS. Passage across BBB:- Main limiting factor for the delivery of potential CNS drugs into the brain parenchyma. BBB is formed from capillary endothelial cells which are very closely joined together that restrict the paracellular diffusion of hydrophilic drugs. The brain posseses effective efflux systems that actively remove solutes from brain tissue creating a great challenge for potential neurotherapeutics. Increased understanding of BBB physiology has led to rational chemistry and biology based drug delivery strategies.
  4. 4. Fig. 1 : Chemistry and biology based approaches toincrease brain delivery of CNS targeted therapeutic agents
  5. 5.  For a drug to readily cross the BBB by passive diffusion – less molecular weight , lipid soluble, neutral and capable of forming less than eight H-bonds with water. Hence prodrug approach is an attractive chemistry based strategy to increase the CNS transport of poorly penetrating therapeutic agents by their chemical modification.
  6. 6. PRODRUG CONCEPTThe term Prodrug or proagent – Introduced in 1958 – Described asbioreversible derivatives of drug molecules that must undergo achemical or enzymatic biotransformation to the active forms withinthe body, prior to exerting a pharmacological action.
  7. 7.  The major goal in Prodrug design is to overcome the various physicochemical, pharmaceutical, biopharmaceutical, and/or pharmacokinetic limitations of parent drug, which otherwise would hinder its clinical use. By applying Prodrug technology, the clinical usefulness of a drug molecule may be enhanced without modifying the pharmacological activity of a parent drug. Prodrug approaches utilize passive drug uptake processes into CNS by chemically modifying a drug to become more lipophilic. Such chemical derivatives are known as Chemical delivery systems (CDSs) and other prodrug approaches are carrier mediated and receptor mediated prodrug transport as well as gene-directed enzyme prodrug therapy.
  8. 8. ROLE OF INCREASEDLIPOPHILICITY IN CNS DRUG DELIVERY A frequent challenge with new drug candidates, in regard to CNS delivery is high polarity. Transcellular diffusion through the cell membranes the only feasible passive route for entering the CNS. This makes adequate lipophilicity one of the key elements in passive CNS entry. A very simple approach to increase the CNS entry of polar molecules would be the masking of polar functionalities within such compounds. This is sometimes referred to as lipidization of molecules. Lipidization through prodrugs offers a possibility for a more efficient CNS delivery of polar drugs.
  9. 9.  Lipidization Approach :• With increased lipophilicity, for example through simple ester prodrugs, increased CNS access due to the more lipophilic nature of the prodrugs.• The general criteria of site specific drug delivery through prodrugs : - The prodrugs must have ready access to the appropriate tissue within the CNS. - Bioconversion back to the parent drug should be highly siteselective, and - The parent drug should exhibit prolonged retention within the target tissue.• Increased lipophilicity through prodrugs does not alone ensure more efficient CNS therapy. It may also lead to concerns of toxicity.• For this, the peripheral bioconversion of the drug should be slow enough to avoid excess premature bioconversion and the CNS bioconversion fast enough to enable therapeutic drug levels within the CNS before prodrug clearance.
  10. 10. The role of BBB efflux transporters in lipophilic prodrug CNS entry
  11. 11. • The figure illustrates the challenge when the parent drug is a substrate for an efflux transporter at the BBB. In the case of prodrug A, an active efflux component combined with a relatively slow bioconversion within the CNS gives only minimum parent drug levels in the CNS.• In the case of prodrug B, the fast bioconversion within the CNS enables substantial levels of parent drug within the CNS, despite the active efflux component.• Increased lipophilicity still remains one of the key aspects that must be taken into an account when developing prodrugs for CNS delivery.• With CNS prodrugs, the target tissue bioconversion needs to both rapid and selective enough to compete with elimination from the target tissue, and also to ensure that the premature bioconversion of the prodrug is low enough.
  12. 12. Chemical Drug Delivery Systems :• A successful prodrug approach that utilizes improved lipophilicity and also requires a sequential bioactivation steps for conversion to an active drug and a brain tissue trapped intermediate is often referred as a chemical drug delivery system.• The CDS term coined by Bodor and coworkers to distinguish this approach from prodrugs that typically require only a single activation step.• The principle of CDS, in addition to providing access to the brain by increasing the lipophilicity of a drug, exploits specific properties of the BBB to lock drugs in the brain on arrival and prevent them from re-crossing the BBB.• CDS exploits the linking of an active drug molecule to a bioremovable lipophilic targetor moiety, 1,4- dihydro-N- methylnicotinic acid, which results in a derivative that readily distributes throughout the body and brain after administration due to its lipophilic character.
  13. 13. ENDOGENOUS TRANSPORTERS IN CNS PRODRUG DELIVERY The BBB expresses several different transport mechanisms that enable the CNS delivery of compounds that are fundamental to the normal functions of the brain. These transporters have become a target to drug or prodrug design in an attempt to ferry drug molecules across the BBB via carrier-mediated transport. The endogenous BBB transporters can therefore be classified into two categories:- - Carrier-mediated transport. - Active efflux transport.
  14. 14.  Carrier-mediated Transport:• Several specific endogenous influx transporters have been identified at the BBB for nutrients, such as amino acids, glucose and vitamins.• Many drug molecules have similar structural properties to endogenous substrates.• Chemical drug modification in a way that the drug can be recognized by specific transporters.• One attractive approach is to conjugate an endogenous transporter substrate to the active drug molecule in a bioreversible manner, i.e., to utilize the prodrug approach.• The prodrug should be recognized by the specific transporter mechanism at the BBB, and more importantly transported across the BBB to brain tissues, where the release of an active drug from the prodrug should take place.
  15. 15.  Large neutral amino acid transporter:- This transport system is expressed on the luminal and abluminal membranes of capillary endothelial cells, and efficiently transports neutral L-amino acids into the brain. Several clinically useful amino acid mimicking drugs, such as gabapentin and melphalan, have been shown to be delivered into the brain predominantly via cerebrovascular LAT1-mediated transport, thus demonstrating the ability of LAT1 to be utilized in drug delivery. The only prodrug that is used clinically for entering the brain predominantly through LAT1-dedicated transport is L-dopa. The conversion of dopamine into its alpha-amino acid, L-dopa, enables the brain to uptake dopamine via LAT1. Example of LAT1 utilizing prodrugs is 4-chlorokynurenine, a prodrug of 7-chlorokynurenic acid. 7-Chlorokynurenic acid is an N-methyl-D-aspartate antagonist that crosses the BBB poorly because of its high hydrophilicity. But conversion into 4-cholorokynurenine enable it to pass through BBB via LAT-1 mediated transport.
  16. 16. OVERCOMING EFFLUX TRANSPORT Transport out of the brain also plays a critical role in efficient drug delivery. Different efflux transporters present in BBB act as clearance systems for compounds and also efflux the incoming drugs thus resulting in low brain interstitial concentration. Important functional groups of drug molecules that afford recognition of efflux transporters could be masked with promoities. Prodrug approach by inhibiting the function of efflux transporters by co-administration of efflux substrate drugs with efflux inhibitors. An efflux inhibitor could also be conjugated with therapeutic drugs to form a co drug.
  17. 17. • Co drug approach explored to improve L-dopa brain delivery with apotent inhibitor entacapone, as a form of L-dopa-entacapone co-drug.• This approach applicable to lipophilic drugs able to cross the BBB,due to their lipophilicity, but restricted from efficient brain entry by effluxtransporters.• Some metabolites causing neuro diseases are cleared from the CNSby efflux systems.• But the chronic inhibition of these efflux systems might lead to anaccumulation of neurotoxins in the brain.• Chronic dosing of efflux inhibitors may possibly upregulate otherefflux systems at the BBB as a compensatory mechanism raisingfurther issues associated with clinical use of these inhibitors.Transporter Substrate InhibitorP-glycoprotein Saquinavir, Vincristine VerapamilMRP1-6 Melphalan, AZT ProbenecidBCRP Topotecan CF 120918Oatp1-3 Rosuvastatin, Enalapril Rifampicin, ProbenecidOATP-A Bile acids RifampicinOAT3 Cephalosporin antibiotics Acyclovir, Probenecid
  18. 18. ANTIBODY AND GENE- DIRECTED PRODRUG THERAPIES• More selective prodrug activation in targeted tissues can be achieved by exogenous prodrug bioconverting enzymes that are delivered via monoclonal antibodies or generated from genes encoding an exogenous enzyme.• These approaches are referred to as ADEPT and GDEPT, and also known as suicide gene therapy, both useful means of targeting prodrugs especially towards various tumors.• Bacterial gene cytosine deaminase, sensitizes tumor cells to the antifungal drug 5-fluorocytosine.• 5-FC is then bioconverted to the anticancer drug, 5- fluorouracil.• However, no significant benefit when compared to standard therapy such as surgical resection and radiotherapy.• Further optimization of gene transfer vectors is essential for improving the clinical effectiveness of GDEPT.
  19. 19. CONCLUSIONS Recent advances in biotechnology and pharmaceutical sciences have greatly expanded the number of drugs that are being developed for the treatment of CNS disorders. However, the BBB presents a major structural and functional barrier for drugs that have pharmacological targets within the brain. A potential option to improve CNS drug delivery is in the utilization of prodrug technology. Prodrugs have already become an integral part of the drug design and delivery processes, it has been estimated that 5-6% of all marketed drugs worldwide are prodrugs; in recent years, approximately 15% of all new approved drugs were prodrugs. There is a strong belief to justify the idea that prodrugs hold great potential for CNS drug delivery. A better understanding of molecular biology will certainly provide more insight in the mechanisms of enzymes and endogenous transporters that exist at the BBB.
  20. 20. REFERENCES W.M. Pardrige. Why is the global CNS Pharmaceutical Market so under-penetrated. Drug Discov. Today. 7(1):5-7(2002), Jan 1 W.M. Pardrige. The Blood-Brain Barrier:Bottleneck in Brain drug development. NeuroRx.2(1):3-14(2005), Jan. D.J. Begley. Delivery of therapeutic agents to the central nervous system:the problems and the possibilities. Pharmacol Ther. 104(1):29-45(2004), Oct. M.W. Bradbury. The structure and function of the blood-brain barrier. Fed. Proc. 43(2):186-190(1984), Feb. R.C. Janzer, and M.C. Raff Astrocytes induce blood-brain barrier properties in endothelial cells. Nature. 325(6101):253- 257(1987).Jan 15-21. J.H.Kim, J.A. Park, et al. Blood-neural barrier: intercellular communication at glio-vascular interface. J.Biochem. Mol. Biol. 39(4) : 339 -345 (2006), Jul 31.
  21. 21. REFERENCES (Contd.) C.H. Lai, and K.H. Kuo. The critical component to establish in vitro BBB model: Pericyte. Brain Res. Rev. 50(2):258-265(2005), Dec 15 D.J. Begley. The blood-brain barrier:Principles for targeting peptides and drugs to the central nervous system. J. Pharm. Pharmacol. 48(2):136-146(1996), Feb. W. Loscher, and H. Potschka. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2(1):86- 98 (2005), Jan. A.H. Schinkel. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv. Drug Deliv. Rev. 36(2-3):179-194(1999), Apr 5. D.J.Begley. ABC transporters and the blood-brain barrier. Curr. Pharm. Des. 10(12):1295-1312(2004) W.M. Pardridge, and W.H. Oldendorf. Transport of metabolic substrates through the blood-brain barrier. J.Neurochem.28(1):5- 12(1977), Jan. A. Albert. Chemical aspects of selective toxicity. Nature. 182:421- 422(1958).

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