Prodrugs site specific

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

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. 

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. 

Drugs may also undergo hydrolysis by intestinal esterases (hydrolases), more specifically carboxylesterases (EC 3.1.1.1) in the intestinal lumen and at the brush border membrane [58, 59]. It has been shown that intestinal hydrolase activity in humans was closer to that of the rat than the dog or Caco-2 cells [60]. In these studies, six propranolol ester prodrugs and p-nitrophenylacetate were used as substrates, and the hydrolase activity found was ranked in the order human > rat Caco-2 cells > dog for intestinal microsomes. The rank order in hydrolase activity for the intestinal cytosolic fraction was rat > Caco-2 cells = human > dog. The hydrolase activity towards p-nitrophenylacetate and tenofovir disoproxil has also been reported in various intestinal segments from rats, pigs and humans. The enzyme activity in intestinal homogenates was found to be both site-specific (duodenum > jejunum > ileum > colon) and species-dependent (rat > man > Pig)-... 

Van Gelder J, Shafiee M, de Clercq E, Penninckx F, Van den Mooter G, Kinget R, Augustijns P (2000b) Species-dependent and site-specific intestinal metabolism of ester prodrugs. Int J Pharm 205 93-100. 

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],... 

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. 

In the design of drugs, the usefulness of renal-specific enzymes which enable the site-specific release of the active drug, should be taken into account. The design of kidney-selective prodrugs is based upon the relatively higher amounts of certain enzymes in the proximal tubular cells than elsewhere in the body. 

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

Unfortunately this approach has not been very successful for producing site specific antitumour drugs. However, site specific prodrugs have been developed to deliver drugs to a number of sites. 

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...

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 prodrug methenamine, described above in this chapter (Scheme S-17), can be considered a site-specific chemical delivery system for the urinary tract antiseptic agent fotmal-dehyde. The low pH of the urine promotes the hydrolysis... 

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