Sulfasalazine metabolites

Von Ritter, C., Grisham, M.B. and Granger, D.N. (1989). Sulfasalazine metabolites and dapsone attenuate formyl-methionyl-leucyl-phenylalanine-induced mucosal injury in rat ileum. Gasteroenterolog 96, 811-816. 

AUgayer, H. and Stenson, W.F. (1988). A comparison of effects of sulfasalazine and its metabolites on the metabolism of endogenous vs. exogenous arachidonic acid. Immunophar-macology 15 39-45. 

Suematsu, M., Suzuki, M., Miura, S., Miura, S., Suzuki, K., Hibi, T., Watanabe, M. and Tsuchiya (1987b). Sulfasalazine and its metabolites attenuate respiratory burst of leukocytes -a possible mechanism of anti-inflammatory effects. J. Clin. Lab. Immunol. 23, 31-33. 

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

Pharmacology The mode of action of sulfasalazine or its metabolites, 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP), is still under investigation but may be related to the anti-inflammatory or immunomodulatory properties that have been observed in animals and in vitro, to its affinity for connective tissue, or to the relatively high concentration it reaches in serous fluids, the liver, and intestinal walls. In ulcerative colitis, the major therapeutic action may reside in the 5-ASA moiety. P.842... 

Excretion - Absorbed SP and 5-ASA and their metabolites are primarily eliminated in the urine either as free metabolites or as glucuronide conjugates. The majority of 5-ASA stays within the colonic lumen and is excreted as 5-ASA and acetyl-5-ASA with the feces. The calculated clearance of sulfasalazine following IV administration was 1 L/h. Renal clearance was estimated to account for 37% of total clearance. 

Intestinal or urinary obstruction porphyria, hypersensitivity to sulfasalazine, its metabolites, salicylates, or sulfonamides. 

Elderly Elderly patients with rheumatoid arthritis showed a prolonged plasma half-life for sulfasalazine, SP, and their metabolites. 

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-... 

Sulfasalazine is composed of sulfapyridine and 5-ASA molecules linked by an azo bond. Sulfapyridine has no effect on the inflammatory bowel disease, and instillation of this agent into the colon does not heal colonic mucosa. It is, however, responsible for most of sulfasalazine s side effects, including sulfa allergic reactions. 5-ASA, the active metabolite, may inhibit the synthesis of mediators of inflammation. 

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. 

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. 

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. 

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-... 

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]. 

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. 

Apart from classic analgesic nephropathy, this chapter will also handle the possible nephrotoxic role of 5-aminosalicylic acid (5-ASA) used in patients with chronic inflammatory bowel disease (IBD). During the last decade, 5-ASA replaced sulfasalazine as first-line therapy for mildly to moderately active IBD. For decades, sulphasalazine, an azo-compound derived from sulphapyridine and 5-aminosalicylic acid (5-ASA), has been the only valuable non-corticosteroid drug in the treatment of inflammatory bowel disease. Azad Kahn et al. [25] showed that the pharmacologically active moiety in sulphasalazine for the treatment of these diseases was 5-ASA. Consequently, this resulted in a number of new 5-ASA formulations (mesalazine, olsalazine, balsalazine) for topical and oral use. Since the metabolite sulphapyridine was largely responsible for the side effects of sulfasalazine, the primary advantage of the newer 5-ASA agents is their improved adverse effect profile. 

Systemically absorbed sulfasalazine is excreted chiefly in urine some parent drug and metabolites are excreted in breast milk. Plasma half-life is about 6 to 8 hours. 

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... 

Sulfasalazine (Azaline) Metabolized to 5-aminosalicylic acid (aspirin) in colon. Metabolite has local antiinflammatory actions. Ulcerative colitis. 

In a study in 5 healthy subjects the conversion and release of the active metabolite of sulfasalazine, 5-aminosalicylic acid was reduced by one third when a single 2-g dose of sulfasalazine was given after a 5-day course of ampicillin 250 mg four times daily. ... 

The azo link of sulfasalazine is split by anaerobic bacteria in the colon to release sulphapyridine and 5-aminosaiicylic acid, the latter being the active metabolite that acts locally in the treatment of inflammatory bowel disease. Antibacterials that decimate the gut flora can apparently reduce this conversion and this is reflected in lower plasma levels. Rifampicin also possibly increases the metabolism of the sulphapyridine. 

Ferrous iron 400 mg reduced the peak serum levels of a single 50-mg/kg dose of sulfasalazine by 40% in 5 healthy subjects. The reasons are not known, but it seems likely that the sulfasalazine chelates with the iron in the gut and thereby interferes with its absorption. The extent to which this suggested chelation affects the ability of the intestinal bacteria to split the sulfasalazine and release its locally active metabolite S-aminosalicylic acid seems not to have been studied. Therefore the effect of this interaction on the clinical response to sulfasalazine is unclear. 

In a randomised, double-blind, placebo-controlled study, 14 healthy subjects were given sulfasalazine 1 g every 12 hours for 8 days, with zileuton 800 mg or a placebo every 12 hours on days 3 to 8. It was found that the pharmacokinetics of the sulfasalazine and its metabolites (sulphapyridine and A/-acetyl sulphapyridine) were not significantly changed. The study did not directly look at the pharmacokinetics of the zileuton but the parameters measured were similar to those seen in a previous study. There would seem to be no reason for special precautions if both drugs are used. 

Awni WM, Braeckman RA, Locke C, Dube LM, Granneman GR. The influence of multiple oral doses of zileuton on the steady-state pharmacokinetics of sulfasalazine and its metabolites, sulfapyridine and N-acetylsulfa yridine Clin Pharmacokinet (1995) 29 (Suf l 2), 98-104. 

Immunologic Cross-reactivity between sulfamethoxazole and sulfasalazine has been studied using in vitro lymphocyte transformation responses in five subjects with severe allergies to either drug (2 and 3 subjects respectively) [124 "]. In all cases lymphocyte transformation was positive to both sulfamethoxazole and sulfapyridine (a metabolite of sulfasalazine), but not to the related non-aromatic sulfonamides furosemide and hydrochlorothiazide. Cross-reactivity can occur between sulfonamide antibiotics and non-antibiotics when there is structural similarity. 

The eight principal metabolites of sulfasalazine (salicylazosulfapyridine. Figure 6.61) have been measured in plasma by direct injection HPLC after protein precipitation with methanol. The analytical column was unmodified silica and the eluent was methanol-aq. potassium phosphate (0.2molL pH 6.5)-water (45 + 10 + 45) containing cetyltrimethylammonium bromide (3.75 mmolL ). Detection was at a GCE (+0.6 V vs Ag/AgCl). 

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