Targeting drugs to the brain by redox chemical delivery systems.
Chemical delivery systems (CDSs) based on the redox conversion of a lipophilic dihydropyridine to an ionic, lipid-insoluble pyridinium salt have been developed to improve the access of therapeutic agents to the central nervous system. A dihydropyridinium-type CDS or a redox analog of the drug is sufficiently lipophilic to enter the brain by passive transport, then undergoes an enzymatic oxidation to an ionic pyridinium compound, which promotes retention in the CNS. At the same time, peripheral elimination of the entity is accelerated due to facile conversion of the CDS in the body. This review discusses chemical, physicochemical, biochemical, and biological aspects in relation to the principles and practical implementation of the redox brain-targeting approach to various classes of drugs. Representative examples to the brain-enhanced delivery of neurotransmitters, steroids, anticonvulsants, antibiotics, antiviral, anticancer and antidementia agents, and neuropeptides and their analogs are presented in detail. In vivo and in vitro studies and preliminary clinical data of several novel derivatives have been promising, which could lead to a practical use of the redox CDSs after proper pharmaceutical development. The investigations accentuate the need for considering physicochemical, metabolic, and pharmacokinetic properties in designing of carrier systems that are able to target drugs into the central nervous system.
Center for Drug Discovery, College of Pharmacy, University of Florida, J. Hillis Miller Health Center, Gainesville, FL 32610, USA. lprokai@grove.ufl.edu
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D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D016503:Drug Delivery Systems; D006801:Humans; D015394:Molecular Structure; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000008:administration & dosage
D004364:Pharmaceutical Preparations