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Review
. 2008;10(1):92-102.
doi: 10.1208/s12248-008-9009-8. Epub 2008 Feb 5.

Prodrug approaches for CNS delivery

Jarkko Rautio  1 , Krista Laine, Mikko Gynther, Jouko Savolainen
Affiliations
Review

Prodrug approaches for CNS delivery

Jarkko Rautio et al. AAPS J. 2008.

Abstract

Central nervous system (CNS) drug delivery remains a major challenge, despite extensive efforts that have been made to develop novel strategies to overcome obstacles. Prodrugs are bioreversible derivatives of drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which subsequently exerts the desired pharmacological effect. In both drug discovery and drug development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents that overcome barriers to a drug's usefulness. This review provides insight into various prodrug strategies explored to date for CNS drug delivery, including lipophilic prodrugs, carrier- and receptor-mediated prodrug delivery systems, and gene-directed enzyme prodrug therapy.

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Figures

Fig. 1
Fig. 1
Chemistry- and biology-based approaches to increase brain delivery of CNS targeted therapeutic agents (modified from Pardridge 2003 (13))
Fig. 2
Fig. 2
A representative illustration of the prodrug concept. The Drug-Promoiety indicates that part of the prodrug is pharmacologically inactive. The Barrier can be any limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance, which must be overcome for the development of a marketable drug (adapted from Rautio et al. 2007 (25))
Fig. 3
Fig. 3
The role of BBB efflux transporters in lipophilic prodrug CNS entry (modified from Anderson 2007 (29))
Fig. 4
Fig. 4
An illustration of the chemical drug delivery system (CDS)
Fig. 5
Fig. 5
Structures of exo- and endogenous LAT1 substrates. All LAT1 substrates have a positively charged amino group, a negatively charged carboxyl group and a hydrophobic side chain
Fig. 6
Fig. 6
Structures of a C-3-glucose dopamine succinyl ester and a C-6-glucose dopamine succinyl ester
Fig. 7
Fig. 7
An outline of antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT) for site-specific activation of cytotoxic drugs in brain tumor cells
See this image and copyright information in PMC

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References

    1. Pardridge W. M. Why is the global CNS pharmaceutical market so under-penetrated. Drug Discov. Today. 2002;7(1):5–7. - PubMed
    1. Pardridge W. M. The blood–brain barrier: bottleneck in brain drug development. NeuroRx. 2005;2(1):3–14. - PMC - PubMed
    1. Begley D. J. Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol Ther. 2004;104(1):29–45. - PubMed
    1. Bradbury M. W. The structure and function of the blood–brain barrier. Fed. Proc. 1984;43(2):186–190. - PubMed
    1. Janzer R. C., Raff M. C. Astrocytes induce blood–brain barrier properties in endothelial cells. Nature. 1987;325(6101):253–257. - PubMed

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