5-Aminosalicylic acid prodrug

U Klotz. Clinical pharmacokinetics of sulfasalazine, its metaboliters and other prodrugs of 5-aminosalicylic acid. Clin Pharmacokin 10 285-302, 1985. 

Fig. 6.11. Peptide prodrugs (6.20, 6.21, and 6.22) for the intestine-selective delivery of 5-aminosalicylic acid (6.23). The prodrugs undergo selective activation by intestinal brush border enzymes, namely aminopeptidase A and/or carboxypeptidases [39].

R. Pellicciari, A. Garzon-Aburbeh, B. Natalini, M. Marinozzi, C. Clerici, G. Gentili, A. Morelli, Brush-Border-Enzyme-Mediated Intestine-Specific Drug Delivery. Amino Acid Prodrugs of 5-Aminosalicylic Acid , J. Med. Chem. 1993, 36, 4201 -4207. 

A medicinal example is found with 5-aminosalicylic acid O-sulfate (5-ASA sulfate, 9.90). 5-ASA is an agent for the treatment of ulcerative colitis and Crohn s disease of the large intestine, but it is unstable in the gastric juice. 5-ASA sulfate was, therefore, developed as a prodrug able to reach its site of action (the colon) following oral application [173]. In healthy human... 

Sulfasalazine is a prodrug of which 70% is converted by colon bacteria to two active metabolites, sulfapyri-dine and 5-aminosalicylic acid (mesalamine). Sulfa-pyridine has antibacterial activities, and 5-aminosali-... 

Another purpose of enteric coating is drug targeting, as in the case of 5-aminosalicylic acid or the prodrugs mesalazine and sulfasalizine. In these cases, enteric coating is applied such that the drug concentration is increased in the lower parts of the GI tract. 

For CES, there appear to be no regional differences in the small intestine for the N-acetyltransferase (NAT) activity [108]. The presence ofboth NAT isozymes has been demonstrated in the human gut mucosa by using the prototypical substrates p-aminobenzoic acid (NAT1) and sulfamethazine (NAT2) [109, 110]. The active metabolites 5-aminosalicylic acid and sulfapyridine of the prodrug sulfasalazine undergo extensive presystemic acetylation in the small intestine [111]. 

Azo Prodrugs Amines have been incorporated into an azo linkage to form prodrugs that can be activated through azo reduction. In fact, sulfa dmgs were discovered because of prontosil (93), an inactive azo dye that was converted in vivo to the active sulfanilamide (95) (Scheme 15). Clinically useful balsalazide (23), olsalazine (25), and sulfasalazine (26) are azo prodrugs of mesalazine (27). They are converted in vivo by bacterial azo reductases in the gut to the active 5-aminosalicylic acid (5-ASA or mesalazine, 27), which is responsible for their anti-inflammatory activity in the treatment of ulcerative colitis, as discussed earlier. 

Sulfasalazine, a prodrug, is cleaved by bacteria in the colon into sulfapyridine and 5-aminosalicylic acid. It is believed that the sul-fapyridine moiety is responsible for the agent s antirheumatic properties, although the exact mechanism of action is not known. Once the colonic bacteria have cleaved sulfasalazine, sulfapyridine and 5-aminosalicylic acid are absorbed rapidly from the gastrointestinal tract. Sulfapyridine distributes rapidly throughout the body, but higher concentrations are found in certain tissues such as serous fluid, liver, and intestines. Both sulfasalazine and its metabolites are excreted in the urine. Antirheumatic effects should be seen within 2 months. 

Callant, D. and Schacht, E. (1990) Macromolecular prodrugs of 5-aminosalicylic acid, 1. Azo-conjugates. Makromol Chem. 191 529-536. 

Figure 2.25 Intestinal bacteria break down the prodrug sulfasalazine into sulfapyridine and the active anti-inflammatory component 5-aminosalicylic acid (5ASA).

Huttunen KM, Tani N, Juvonen RO, Raunio H, Rautio J (2013) Design, synthesis, and evaluation of novel cyclic phosphates of 5-aminosalicylic acid as cytochrome p450-activated prodrugs. Mol Pharm 10 532-537... 

Jung, Y. J. Lee, Jeoung S. Kim, Y. M. Colon-specific prodrugs of 5-aminosalicylic acid synthesis and in vitro/in vivo properties of acidic amino acid derivatives of 5-aminosalicylic acid. J. Pharm. Sci. 2001, 90, 1767-1775. 

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