» Articles » PMID: 1685664

Direct and Metabolism-dependent Toxicity of Sulphasalazine and Its Principal Metabolites Towards Human Erythrocytes and Leucocytes

Overview
Specialty Pharmacology
Date 1991 Sep 1
PMID 1685664
Citations 6
Authors
Affiliations
Soon will be listed here.
Abstract

1. The role of metabolites in sulphasalazine-mediated toxicity has been investigated in vitro by the use of human red blood cells and mononuclear leucocytes as target cells, with methaemoglobin formation and cytotoxicity respectively, being the defined toxic end-points. 2. Of the metabolites of sulphasalazine investigated, only sulphapyridine was bioactivated by human liver microsomes in the presence of NADPH to a metabolite which caused marked methaemoglobinaemia and a small, but statistically significant degree of mononuclear leucocyte cell death. 3. Methaemoglobinaemia was inhibited by ketoconazole but not by ascorbic acid (100 microM), glutathione (500 microM) and N-acetylcysteine (50 microM). In contrast, ascorbic acid and the thiols afforded complete protection for mononuclear leucocytes. 4. Sulphapyridine (100 microM) was converted in vitro to a metabolite (metabolite conversion 6.8 +/- 0.3%), the retention time of which on h.p.l.c. corresponded to synthetic sulphapyridine hydroxylamine. The half-life of sulphapyridine hydroxylamine in phosphate buffer (pH 7.4) was found to be 8.1 min. 5. In the absence of microsomes and NADPH, sulphapyridine hydroxylamine caused a concentration-dependent (10-500 microM) increase in methaemoglobinaemia (2.9%-24.4%) and cytotoxicity (5.4%-51.4%), whereas sulphasalazine, sulphapyridine, 5-hydroxy sulphapyridine and 5-aminosalicylic acid had no effect.

Citing Articles

Successful Treatment of Linear IgA Disease and Ulcerative Colitis With Sulfasalazine.

Fletcher D, Patel S, Motaparthi K Cureus. 2023; 15(4):e37210.

PMID: 37168182 PMC: 10166405. DOI: 10.7759/cureus.37210.


Checkpoint Inhibition Reduces the Threshold for Drug-Specific T-Cell Priming and Increases the Incidence of Sulfasalazine Hypersensitivity.

Hammond S, Olsson-Brown A, Grice S, Gibson A, Gardner J, Castrejon-Flores J Toxicol Sci. 2021; 186(1):58-69.

PMID: 34850240 PMC: 8883351. DOI: 10.1093/toxsci/kfab144.


Sulfasalazine-Induced Agranulocytosis Is Associated With the Human Leukocyte Antigen Locus.

Wadelius M, Eriksson N, Kreutz R, Bondon-Guitton E, Ibanez L, Carvajal A Clin Pharmacol Ther. 2017; 103(5):843-853.

PMID: 28762467 PMC: 5947520. DOI: 10.1002/cpt.805.


Mechanism of action of 5-arninosalicylic acid.

Punchard N, Greenfield S, Thompson R Mediators Inflamm. 1992; 1(3):151-65.

PMID: 18475455 PMC: 2365334. DOI: 10.1155/S0962935192000243.


Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity.

Naisbitt D, Hough S, Gill H, Pirmohamed M, Kitteringham N, Park B Br J Pharmacol. 1999; 126(6):1393-407.

PMID: 10217534 PMC: 1565922. DOI: 10.1038/sj.bjp.0702453.


References
1.
Das K, Dubin R . Clinical pharmacokinetics of sulphasalazine. Clin Pharmacokinet. 1976; 1(6):406-25. DOI: 10.2165/00003088-197601060-00002. View

2.
Fischer C, Klotz U . Determination of sulfapyridine and its major metabolites in plasma by high pressure liquid chromatography. J Chromatogr. 1978; 146(1):157-62. DOI: 10.1016/s0378-4347(00)81302-x. View

3.
Wallace I . Neurotoxicity associated with a reaction to sulphasalazine. Practitioner. 1970; 204(224):850-1. View

4.
Das K, Eastwood M, MCMANUS J, Sircus W . Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. N Engl J Med. 1973; 289(10):491-5. DOI: 10.1056/NEJM197309062891001. View

5.
Pounder R, Craven E, Henthorn J, Bannatyne J . Red cell abnormalities associated with sulphasalazine maintenance therapy for ulcerative colitis. Gut. 1975; 16(3):181-5. PMC: 1410952. DOI: 10.1136/gut.16.3.181. View