Prodrugs site-specific delivery

Tissue-selective activation of classical prodrugs Site-specific delivery of ad hoc chemical systems... 

Numerous reports of prodrugs in the literature show improved drug effects. Prodrugs that have shown some measure of success for site-specific delivery include L-3,4-dihydroxyphenylalanine (L-dopa) to the brain [56], dipivaloyl derivative of epinephrine to the eye [57], /-glutamyl-L-dopa to the kidney [58], fi-n-glucoside dexamethasone and prednisolone derivatives to the colon [59], thiamine-tetrahydrofuryldisulfide to red blood cells, and various amino acid derivatives of antitumor agents such as daunorubicin [61,62], acivicin [63], doxorubicin [63], and phenylenediamine [63] to tumor cells. 

Classical carrier-linked prodrugs Site-specific chemical delivery systems Macromolecular prodrugs Drug-antibody conjugates... 

J. Takata, Y. Karube, M. Hanada, K. Matsunaga, Y. Matsushima, T. Sendo, T. Aoyama, Vitamin K Prodrugs 1. Synthesis of Amino Acid Esters of Menahydroquinone-4 and Enzymatic Reconversion to an Active Form , Pharm. Res. 1995, 12, 18-23 J. Takata, Y. Karube, M. Hanada, K. Matsunaga, Y. Matsushima, T. Sendo, R. Oishi, Vitamin K Prodrugs 2. Water-Soluble Prodrugs of Menahydroquinone-4 for Systemic Site-Specific Delivery , Pharm. Res. 1995, 12, 1973- 1979. 

Various formulation concepts have been introduced as potential ways to protect peptide and protein drugs from the hostile GI environment to increase their oral absorption such as use particulate drug carriers (microspheres, lipo-somes, and lectins), coadministration of enzyme inhibitors and absorption enhancers, use of chemical modification (prodrug), and site-specific delivery to the colon or rectum. Some of these approaches are discussed later. 

The body provides an intensely chiral environment in which the great majority of important processes exhibit stereospecificity. The disposition of xenobiotics is determined by their interaction with highly chiral endogenous molecules such as transporters and enzymes. Therefore the site-specific delivery of a drug can be achieved through the prodrug approach... 

V. J. Stella and K. J. Himmelstein, Critique of prodrugs and site-specific drug delivery, in Optimization of Drug Delivery, Alfred Benzon Symposium 17 (H. Bundsgaard, A. B. Hansen, and H. Kofod, eds.), Munksgaard, Copenhagen, 1982, p. 134. 

VJ Stella, KJ Himmelstein. Prodrugs and site-specific drug delivery. J Med Chem 23 1275-1282, 1980. 

A special group of carrier-linked prodrugs are the site-specific chemical delivery systems [23], Macromolecular prodrugs are synthetic conjugates of drugs covalently bound (either directly or via a spacer) to proteins, polypeptides, polysaccharides, and other biodegradable polymers [24],... 

N. Bodor and J. J. Kaminski, Prodrugs and site-specific chemical delivery systems, Annu. Rep. Med. Chem. 22 303 (1987). 

Figure 16.2 Dihydropyridine-pyridinium salt redox system for site-specific and sustained delivery to the brain. The prodrug A is delivered directly to the brain, where it is oxidized and trapped as the prodrug B. The quaternary ammonium salt is slowly cleaved by chemical/enzymatic action with sustained release of the biologically active phenylethylamine C and the facile elimination of the carrier molecule D. Elimination of the drug from the general circulation is by comparison accelerated, either as A or B or as cleavage products...

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