Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

The blood-brain barrier efficiently controls the entry of drug molecules into the brain. We describe a feasible means to achieve carrier-mediated drug transport into the rat brain via the specific, large neutral amino acid transporter (LAT1) by conjugating a model compound to L-tyrosine. A hydrophilic drug, ketoprofen, that is not a substrate for LAT1 was chosen as a model compound. The mechanism and the kinetics of the brain uptake of the prodrug were determined with an in situ rat brain perfusion technique. The brain uptake of the prodrug was found to be concentration-dependent. In addition, a specific LAT1 inhibitor significantly decreased the brain uptake of the prodrug. Therefore, our results reveal for the first time that a drug-substrate conjugate is able to transport drugs into the brain via LAT1.

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.

Paracetamol permeates readily into the cerebrospinal fluid of children. This fast and extensive transfer enables the rapid central analgesic and antipyretic action of intravenous paracetamol.

An efficient five-step synthetic route was developed for full N-substitution of chitosan with a quaternary betaine moiety. The developed synthetic procedure can also be controlled to produce chitosan N-betainates having lesser degrees of substitution. 6-O-Triphenylmethylchitosan, which is highly soluble in organic solvents, was used as an intermediate for N-acylation reactions. Intermediate products were characterized by 13 C CP/MAS NMR, FT-IR, and elemental analysis. The water-soluble quaternary chitosan N-betainates were thoroughly characterized by 1 H NMR and 13 C NMR and by 2D 1 H-1 H COSY NMR and 13 H-1 H HSQC NMR. Degrees of substitution were determined from the 1 H NMR spectra. A significant degradation of the polysaccharide backbone during the synthetic procedure was determined by GPC with a light scattering detector. Experimental SectionMaterials. Chitosan, used as a starting material, was donated by Primex ehf (Reykjavik, Iceland). Weight-average molar mass (Mw) 148 200 Da and number-average molar mass (Mn) 94 200 were determined by GPC-LS. The degree of deacetylation (85%) was confirmed by 1 H NMR. All other chemicals used were commercially available and used as received. Pyridine was distilled over KOH. Dialysis membrane (M w cutoff 12 kDa) was purchased from Sigma (St. Louis, MO).Characterization. 1 H and 13 C spectra were recorded on a Bruker AVANCE DRX 500, operating at 500.13 and 125.76 MHz, respectively. Samples of chitosan N-betainates (40 mg) were dissolved in 600 µL of D 2O. Chemical shifts (δ) are