Sulfapyridine metabolism

Sulfasalazine is absorbed in the proximal intestine and is then excreted unchanged in the bile. In consequence most of orally administred sulfasalzine reaches the colon as such. It is then split by the intestinal flora into its components sulfapyridine, a sulfonamide antimicrobial agent, and 5-aminosalicylic acid (5-ASA). It has been proven that in inflammatory bowel disease 5-ASA is responsible for the beneficial effects while the sulpha component only contributes to the adverse reaction profile. Although some 5-ASA is absorbed and excreted in urine with a half-life of 0.5-1.5 hours, most is eliminated unchanged in the faeces. Sulfapyridine is to a major extend reabsorbed, metabolized in the liver and excreted in the urine with a half-life, depending on the acetylator phenotype, between 5 and 15 hours. 

Sulfasalazine is metabolized to sulfapyridine and 5-aminosalicylic acid, and it is thought that the sulfapyridine is probably the active moiety when treating rheumatoid arthritis (unlike inflammatory bowel disease, see Chapter 62). Some authorities believe that the parent compound, sulfasalazine, also has an effect. In treated arthritis patients, IgA and IgM rheumatoid factor production are decreased. Suppression ofT-cell responses to concanavalin and inhibition of in vitro -cell proliferation have also been documented. In vitro studies have shown that sulfasalazine or its metabolites inhibit the release of inflammatory cytokines, including those produced by monocytes or macrophages, eg, interleukins-1, -6, and -12, and TNF-a. These findings suggest a possible mechanism for the clinical efficacy of sulfasalazine in rheumatoid arthritis. 

Of the azo compounds, 10% of sulfasalazine and less than 1% of balsalazide are absorbed as native compounds. After azoreductase breakdown of sulfasalazine, over 85% of the carrier molecule sulfapyridine is absorbed from the colon. Sulfapyridine undergoes hepatic metabolism (including acetylation) followed by renal excretion. By contrast, after azoreductase breakdown of balsalazide, over 70% of the carrier peptide is recovered intact in the feces and only a small amount of systemic absorption occurs. 

Metabolism The sulfas are acetylated at N4, primarily in the liver. The product is devoid of antimicrobial activity, but it retains the toxic potential to precipitate at neutral or acidic pH, causing crys-talluria ( stone formation ) and therefore potential damage to the kidney (Figure 29.4). Sulfasalazine is effective in the treatment of inflammatory bowel disease because local intestinal flora split the drug into sulfapyridine and 5-aminosalicylate. The latter exerts the antiinflammatory effect. Absorption of sulfapyridine can lead to toxicity in patients who are slow acetylators. 

The metabolism of a number of sulfonamides, such as sulfanilamide. sulfamethoxazole (Gantanol). sulfisoxa-zx>le (Gantrisin). sulfapyridine (major metabolite from azo reduction of sulfasalazine. Azulfidine), and sulfamethazine. " " occurs mainly by acetylation at the N-4 position. With sulfanilamide, acetylation also takes place at the sul-... 

Das KM, Eastwood MA, McManus JP, Sircus W (1973) Adverse reactions during salicylazo-sulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. N Engl J Med 289 491-495... 

Sulfasalazine is absorbed poorly from the GI tract after oral administration 70 to 90% is transported to the colon where intestinal flora metabolize the drug to its active ingredients, sulfapyridine (antibacterial) and 5-aminosalicylic acid (antiinflammatory), which exert their effects locally. 

Reduction. Reduction, for example azo- and nitro-reduc-tion, is a less common pathway of drug metabolism. Reductase activity is found in the microsomal fraction and in the cytosol of the hepatocyte. Anaerobic intestinal bacteria in the lower gastrointestinal tract are also rich in these reductive enzymes. A historical example concerns Prontosil, a sulfonamide prodrug. It is metabolized by azo-reduction to form the active metabolite, sulfanilamide. Sulfasalazine is also cleaved by azoreduction by intestinal bacteria to form aminosalicylate, the active component, and sulfapyridine. Chloramphenicol is metabolized by... 

Not understood. Sulfasalazine is broken down in the colon to a sulfonamide, sulfapyridine, and 5-aminosalicylic acid (mesalazine). Some sulfonamides , (p.376) are known inhibitors of warfarin metabolism, and increase the effects of warfarin. In contrast, in the case with sulfasalazine a marked decrease was noted. 

These glucuronides have the necessary p )p< rtieK for extensive hiliarj excretion and their formation probably accounts for the higher biliary excretion of sulfapyridine and sulfamethoxypyridazine compared to the other sulforiamid( s in Table VII, which are not metabolized to polar conjugates of molecular weight of 300 or more. 

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