1. PRODRUG
APPROACHES FOR
CNS DRUG DELIVERY
Review 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. CONTENTS
I. Introduction
II. Prodrug Concept
III. Role of Increased Lipophilicity In CNS
Drug Delivery
IV. Endogenous Transporters In CNS
Prodrug Delivery
V. Overcoming Efflux Transport
VI. Antibody And Gene-Directed Prodrug
Therapies
VII. Conclusions
VIII. References

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. Fig. 1 : Chemistry and biology based approaches to
increase brain delivery of CNS targeted therapeutic agents

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. PRODRUG CONCEPT
The term Prodrug or proagent – Introduced in 1958 – Described as
bioreversible derivatives of drug molecules that must undergo a
chemical or enzymatic biotransformation to the active forms within
the body, prior to exerting a pharmacological action.

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. ROLE OF INCREASED
LIPOPHILICITY 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.  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. The role of BBB efflux transporters in lipophilic prodrug CNS entry

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. 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.

14. 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.

15.  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.

16.  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.

18. 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.

19. • Co drug approach explored to improve L-dopa brain delivery with a
potent 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 efflux
transporters.
• Some metabolites causing neuro diseases are cleared from the CNS
by efflux systems.
• But the chronic inhibition of these efflux systems might lead to an
accumulation of neurotoxins in the brain.
• Chronic dosing of efflux inhibitors may possibly upregulate other
efflux systems at the BBB as a compensatory mechanism raising
further issues associated with clinical use of these inhibitors.
Transporter Substrate Inhibitor
P-glycoprotein Saquinavir, Vincristine Verapamil
MRP1-6 Melphalan, AZT Probenecid
BCRP Topotecan CF 120918
Oatp1-3 Rosuvastatin, Enalapril Rifampicin, Probenecid
OATP-A Bile acids Rifampicin
OAT3 Cephalosporin antibiotics Acyclovir, Probenecid

20. 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.

21. 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.

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