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Immunomodulating Agents in Gastrointestinal Disease
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Samir A. Shah, Athos Bousvaros, A. Christopher Stevens
In 1972, Peppercorn and Goldman identified the mechanism by which Azulfidine is catabolized [3]. By measuring stool and serum concentrations of Azulfidine, 5-ASA, and sulfapyridine in normal and bacteria-free mice, they established that coliform bacteria were necessary for reducing Azulfidine to 5-ASA and sulfapyri-dine through the enzymatic activity of azoreductase. On oral ingestion, Azulfidine is partially absorbed in the jejunum, the majority excreted intact into bile and delivered back to the intestinal lumen. Only a minority of absorbed Azulfidine is excreted in the urine. On reaching the large intestine, Azulfidine is reduced by the bacterial enzyme azoreductase to 5-ASA and sulfapyridine. The 5-ASA moiety is poorly absorbed from the colon and is largely excreted in the stool. In contrast, sulfapyridine is rapidly absorbed from the colon, metabolized by the liver, and excreted in the urine with only small amounts remaining in the stool. If ingested separately, both 5-ASA and sulfapyridine are absorbed in the proximal small intestine, metabolized by the liver, and excreted into the urine, with only a small fraction of either compound reaching the colon. Olsalazine also contains an azo bond that is similarly reduced by colonic bacteria to release two 5-ASA molecules in the colon.
Dietary Fibers And Colon Cancer*
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
Intestinal microflora may convert both endogenous and exogenous agents into active luminal carcinogens, and these microbes appear to be sensitive to various dietary substrates, including fiber-containing foods.68 Changes in the metabolic activity of certain bacteria could occur without changes in the number or types of intestinal bacteria. Diet-induced changes in several fecal enzymes, including nitroreductase, azoreductase, and β-glucuronidase, have been reported.62,68,69 Some could be important in the metabolism of certain environmental carcinogens. However, the role that each fiber polymer might play in the induction or repression of bacterial enzymatic activity has been the subject of only limited study. Preliminary studies indicate that lower bacterial counts are present in fiber polymer-fed (cellulose or pectin) animals and that dimethylhydra-zine administration itself may alter the microbial flora.70 Different effects on fecal β-glucuronidase and β-glucosidase activities were observed between cellulose- and pectin-fed animals.71 Moreover, dimethylhydrazine administration also appeared to alter the activities of these fecal enzymes.71 Further in vivo correlations with actual tumor incidence are now required.
General toxicology
Published in Timbrell John, Study Toxicology Through Questions, 2017
A10. Possible routes of metabolism for the veterinary drug are shown in the figure below (page 76). (a) Azoreductase; (b) esterase; (c) acetyl CoA transferase and ligase; (d) alcohol dehydrogenase; (e) aldehyde dehydrogenase; (f) cytochrome P450; (g) epoxide hydrolase; (h) glutathione-S-transferase; (i) glucuronosyltransferase or sulphotransferase.
Interaction of drugs with gut microbiota modulators
Published in Drug Metabolism Reviews, 2023
Gut microbiota produce a variety of reductases such as azoreductase and nitroreductase. Gut bacterial azoreductases transform azo compounds under an anaerobic condition in the GI tract. Orally administered prontosil and neoprotosil are transformed to sulfanilamide in the intestine (Gingell et al. 1971; Kim 2015). However, the metabolism of orally administered prontosil and neoprotosil into sulfanilamide is suppressed in vivo by treatment with antibiotics, which shifts gut microbiota composition and quantity (Gingell et al. 1971). Gut microbiota convert sulfasalazine and balsalazide to 5-aminosalicylic acid, which is further metabolized to acetylated mesalazine by gut microbiota (Chan et al. 1983; Klotz 1985). However, antibiotics suppress these modifications such as azo reduction and acetylation and their effectiveness in vivo through the gut microbiota alteration (Chan et al. 1983; Klotz 1985).
Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Nada H. El-Dershaby, Soad A. El-Hawash, Shaymaa E. Kassab, Hoda G. Dabees, Ahmed E. Abdel Moneim, Ibrahim A. Abdel Wahab, Mohammad M. Abd-Alhaseeb, Mostafa M. M. El-Miligy
All the newly synthesised compounds were evaluated for their in vitro antibacterial activities against the human pathogens: Staphylococcus aureus (RCMB 0100183), Staphylococcus epidermidis (RCMB 0100183), Streptococcus mutans (RCMB 0100172), and Bacillus subtilis (RCMB 0100162) as examples of Gram-positive bacteria and Pseudomonas aeruginosa (RCMB 0100243), Escherichia coli (RCMB 010052), Salmonella typhi (RCMB 0100104), Shigella dysenteriae (RCMB 0100542) and Proteus vulgaris (RCMB 010085) as examples of Gram-negative bacteria using Ampicillin and levofloxacin as standard Gram-positive and Gram-negative antibacterial agents respectively[6] (Table 5, page S5 supplementary file) see experimental section. The results showed that, most of the tested compounds did not exhibit significant in vitro antibacterial activity, whereas compounds (5 b, 5i, 5j, 5k, 5 m, 5n, and 5o) displayed weak in vitro antibacterial activity this could be assigned to the fact that the investigated compounds were azo co-drugs. Hence, metabolic biotransformation by azo-reductase enzyme into their active metabolites is a requirement for expressing their activities.
Successes, failures, and future prospects of prodrugs and their clinical impact
Published in Expert Opinion on Drug Discovery, 2019
The success of prodrugs in the management of GIT conditions is well established. Sulfasalazine (1 in Figure 1) is indicated for the treatment of ulcerative colitis and Crohn’s disease. It is a prodrug metabolized by intestinal bacteria azo-reductase. The azo bond in the prodrug is cleft producing two active metabolites: 5-aminosalicylic acid (5-ASA) and sulfapyridine [33]. Similarly, balsalazide (2 in Figure 1) also contains an azo bond cleavable by intestinal bacteria azo-reductase. Upon metabolism, balsalazide produces 5-ASA and 4-aminoenzoil-β-alanine. While balsalazide exhibits similar therapeutic activity to sulfasalazine, it has been reported to be better tolerated [34]. Olsalazine (3 in Figure 1) also contains the same linkage and is cleft by the same mechanism. Though, it produces 2 molecules of 5-ASA. The therapeutic efficacy of olsalazine is comparable to that of sulfasalazine and balsalazide, however, it is better tolerated [35].