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The electrochemical properties of a colon-targeted prodrug of 5-aminosalicylic acid (5-ASA), 2-hydroxy-5-[(4-sulfophenyl)azo]benzoic acid (SPSA), were investigated in aqueous solutions at glassy carbon electrodes using cyclic voltammetry and controlled potential electrolysis. The influence of the pH and experimental time domain on the reaction pathway has been studied. The electrochemical reduction of SPSA is identified as an ECE process always leading to the cleavage of azo bond. In an acidic media SPSA is reduced in a 4e(-)/4H(+) process yielding 5-ASA and sulfanilic acid. In neutral and weakly basic media SPSA is reduced in 2e(-)/2H(+) process resulting in the hydrazo intermediate that is stable enough to enable its reoxidation back to SPSA in the time scale of the cyclic voltammetry.
The use of 5-aminosalicylic acid in assessment of reactive oxygen species formation was investigated by in vitro Fenton and ozonation reactions, and by in vivo ozone-exposure experiments. Enzymatic hydroxylation was evaluated by a microsomal assay. Fischer 344 male rats (250 g) injected with 5-aminosalicylic acid (100 mg x kg(-1) i.p.; 30 min) were exposed to ozone (0, 1, 2 ppm; nose only, 2 h); bronchoalveolar lavage, lung homogenates, and plasma were recovered. Oxidation products of 5-aminosalicylic acid were as follows: salicylic acid, by deamination; 2,3-dihydroxybenzoic acid and 2,5-dihydroxybenzoic acid, from radical or enzymatic hydroxylation; 5-amino-2-hydroxy-N,N'-bis(3-carboxy-4-hydroxyphenyl)-1,4-benzoquinonediimine, a condensation product of oxidized 5-aminosalicylic acid; and 5-amino-2,3,4,6-tetrahydroxybenzoic acid, attributed to hydroxyl radical attack without deamination, identified by HPLC electrochemical (HPLC-EC) detector system analysis and by GC-MS analysis of trimethylsilyl derivatives. 5-Aminotetrahydroxybenzoic acid was not formed enzymatically. 5-Aminotetrahydroxybenzoic acid, but not 5-aminosalicylic acid, was significantly elevated in bronchoalveolar lavage (+86%) and lung homogenates (+56%) in response to 2 ppm ozone (p < 0.05); no significant changes were detected in plasma. The data indicate that hydroxylation of 5-aminosalicylic acid is a potential specific probe for in vivo oxidative stress.
Derivatives of 5-aminosalicylic acid (5-ASA) used for the treatment of inflammatory bowel disease may induce acute pancreatitis of immunoallergic origin. 4-aminosalicylic acid (4-ASA) differs from its 5-ASA counterpart by the position of the NH2 group and has shown efficacy in ulcerative colitis. The risk of cross intolerance reaction between 5-ASA and 4-ASA has currently never been evaluated. We report three cases of 5-ASA-induced pancreatitis, with no recurrence of pancreatitis during subsequent treatment with 4-ASA enemas. We conclude that 4-ASA enemas are a safe and well-tolerated therapeutic alternative whenever 5-ASA-induced pancreatitis occurs.
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BACKGROUND: Mesalazine (5-aminosalicylic acid)-containing formulations, designed to optimize drug delivery to the ileo-caecal region, represent a cornerstone in the treatment of inflammatory bowel diseases. AIM: : To test, by means of pharmaco-scintigraphy, whether novel mesalazine-containing pellets release 5-aminosalicylic acid in the same target region as mesalazine tablets (Salofalk). METHODS: Fourteen healthy male volunteers received a single dose of either pellets or tablets containing 500 mg of mesalazine and 2 mg of 152Sm2O3 with a 1-week washout period. The gastrointestinal transit of 153Sm, incorporated into the formulations, was followed by gamma-scintigraphy. Mesalazine release was verified by assessing 5-aminosalicylic acid plasma pharmacokinetics. RESULTS: The formulations reached the ileo-caecal target region almost at the same time (3.3 +/- 1 and 3.8 +/- 1 h for pellets and tablets, respectively). Plasma 5-aminosalicylic acid tmax values were comparable and corresponded to the time during which the formulations were located in the target region. Plasma AUC values were significantly lower for pellets, which might be explained by a more prolonged release of 5-aminosalicylic acid. CONCLUSIONS: Novel mesalazine pellets and Salofalk tablets release active 5-aminosalicylic acid in the same target region and pass through the gastrointestinal tract under fasting conditions in healthy volunteers in a comparable time. From a comparison of in vitro dissolution and plasma concentration data, a slower and more prolonged release of 5-aminosalicylic acid from pellets is suggested.
UV-irradiation (254 nm, 10 or 20 J/cm2) of p-aminobenzoic acid (PABA) and p-aminosalicylic acid (NaPAS) potentiated their antimutagenicity towards N-methyl-N'-nitro-N-nitrosoguanidine mutagenesis in Salmonella typhimurium. Their inhibitory action towards the formation of the mutagen N-methyl-N-nitrosourea from the nitrosation mixture of N-methylurea and nitrite was also increased by UV-irradiation. In contrast, UV-irradiated PABA exhibited no inhibitory effects towards the mutagenicity of sodium azide or 3-azidoglycerol. Neither PABA nor NaPAS nor their UV-irradiation products were themselves mutagenic in the Ames assay.
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A prodrug of 5-aminosalicylic acid (5-ASA), salicylazosulfanilic acid (SASA), which consists of sulfanilic acid linked to 5-ASA through an azo-linkage was newly synthesized. Biopharmaceutical properties of SASA were evaluated in comparison with those of salicylazosulfapyridine (SASP) in rats. Since SASA is much more hydrophilic than SASP, the absorption of SASA from the small intestine was less in comparison with SASP. When SASA and SASP were incubated with the rat intestinal contents under anaerobic conditions, both compounds were stable in the small-intestinal contents, but were rapidly degraded to 5-ASA in the cecal and the colonic contents. The degradation to 5-ASA by the large-intestinal contents was suppressed by the pretreatment with kanamycin sulfate, suggesting that the bioconversion of SASA is mediated by the intestinal microflora similarly to that of SASP and that SASA is also a prodrug of 5-ASA. After the oral administration, 5-ASA was found neither in the stomach nor in the small intestine in case of both prodrugs. Most of the prodrugs were transferred to the lower intestine where they were degraded to 5-ASA. The recovery of SASA including the metabolites from the gastrointestinal tract at four hours after the oral administration was significantly greater than that of SASP. Accordingly, SASA is free from the liberation of sulfapyridine, the adverse effect moiety of SASP, and less absorbable in the small intestine. Thus, the beneficial characteristics of SASA as an excellent colon-targeted prodrug of 5-ASA were clarified.
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