Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
Therapeutic benefit of sulfasalazine in ulcerative colitis and Crohn’s Disease appears to be due to a local action of the sulfasalazine and its split product 5-aminosalicylic acid on the mucous membrane and deeper colonic structures. Pharmacological actions noted for these compounds include inhibition of neutrophil activation, free radical scavenging, inhibition of superoxide production, inhibition of bacterial growth. Sulfasalazine inhibits 15-Prostaglandin dehydrogenase and slows prostaglandin metabolism. Lipoxygenase release in inflammatory cells is also depressed. NK cells and T cell proliferation are inhibited.
There are considerable individual differences in the retention time of suppositories in volunteer studies. Consequently uptake values vary widely also. Given that the effect of the drug is almost certainly due to a local effect pharmacokinetics becomes less relevant to therapeutic action than to possible adverse effects related to systemic levels.
A study of five volunteers over three days following insertion of 2 × 0.5 g suppositories gave the following results:
Retention time: mean 8.9 hours (s.d. 5.2), serum concentration at 10 hours: sulfasalazine 1.7 mcg/ml (s.d. 0.46), sulfapyridine less than 1 mcg/ml. Percentage renal excretion: 10.2 (s.d. 4.3). Uptake as reflected by excretion is much below that of the oral rate and may explain the good tolerance of the dose form.
In two-year carcinogenicity studies in rats and mice, sulfasalazine showed some evidence of carcinogenicity. In rats, there was a small increase in the incidence of transitional cell papillomas in the urinary bladder and kidney. The tumours were judged to be induced mechanically by calculi formed in the urine rather than through a direct genotoxic mechanism. In the mouse study, there was a significant increase in the incidence of hepatocellular adenoma or carcinoma. The mechanism of induction of hepatocellular neoplasia has been investigated and attributed to species-specific effects of sulfasalazine that are not relevant to humans.
Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) or in the L51784 mouse lymphoma cell assay at the HGPRT gene. It did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, and in vivo mouse bone marrow chromosomal aberration tests were negative. However, sulfasalazine showed positive or equivocal mutagenic responses in rat and mouse micronucleus assays, and in human lymphocyte sister chromatid exchange, chromosomal aberration and micronucleus assays. The ability of sulfasalazine to induce chromosome damage has been attributed to perturbation of folic acid levels rather than to a direct genotoxic mechanism.
Based on information from non-clinical studies, sulfasalazine is judged to pose no carcinogenic risk to humans. Sulfasalazine use has not been associated with the development of neoplasia in human epidemiology studies.
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