Prodrugs sulfasalazine

The prodrug sulfasalazine (SAS), used in the treatment of Crohn s disease, uleerative eolitis, and rheumatoid arthritis, is the earliest example of targeted drug delivery in... 

Figure 2 Three examples of 5-amino salicylic acid prodrugs sulfasalazine (I), olsala-zine (II), and balsalazine (III).

Thiopurines are metabolized by thiopurine methyltransferase, whose activity is controlled by a common genetic polymorphism in the short arm of chromosome 6. Patients with low or intermediate activity who take azathioprine or 6-mercaptopurine are at risk of myelosup-pression caused by excess accumulation of the active thiopurine metabolite 6-thioguanine nucleotide. Benzoic acid derivatives, such as mesalazine and its precursors, and prodrugs (sulfasalazine, olsalazine, and balsalazide) inhibit thiopurine methyltransferase activity in vitro. This action could explain the increase in whole blood concentrations of 6-thioguanine nucleotide, leading to leukopenia. 

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]. 

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

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

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-... 

Prodrugs are drug substances that are biotransformed in the body to active metabolites and chemotherapeutic agents. Examples include sulfasalazine to sul-fapyridine, phenylbutazone to oxy-phenbutazone, aspirin to salicylate, and heta-cillin to ampicillin. In some cases, such as aspirin (ester) and hetacillin (amide), hydrolysis in water releases the active drug moiety contained within the basic structure of the prodrug. 

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. 

Because the mechanism of action of sulfasalazine is not related to the sulfapyridine component, and since sulfapyridine is believed to be responsible for many of the adverse reactions to sulfasalazine, mesalamine alone can be used. Mesalamine can be used topically as an enema for the treatment of proctitis, or given orally in slow-release formulations that deliver mesalamine to the small intestine and colon (Table 34—5 and Fig. 34-1). Slow-release oral formulations of mesalamine such as Pentasa release mesalamine from the duodenum to the ileum, with about 75% of the drug passing into the colon. Olsalazine is a dimer of two 5-aminosalicylate molecules linked by an azo bond. Mesalamine is released in the colon after colonic bacteria cleave olsalazine. Balsalazide is a mesalamine prodrug that is enzymatically cleaved in the colon to produce mesalamine. The recommended daily doses of the oral mesalamine derivatives are intended to approximate the molar equivalent of mesalamine present in 4 g of sulfasalazine. At present, snlfasalazine is nsed in preference to oral mesalamine derivatives, mainly becanse it costs mnch less. However, it is not tolerated as well as the mesalamine altematives. Becanse the oral mesalamine formulations are coated tablets or grannies, they should not be crushed or chewed. 

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. 

Sulfasalazine used as prodrug of salicylate in ulcerative colitis and rheumatoid arthritis... 

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... 

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