Acetylator phenotype and adverse effects of sulphasalazine in healthy subjects

Abstract

SUMMARY Sulphasalazine (salicyl-azo-sulphapyridine) was ingested by 27 healthy subjects for five days at a dosage of 4 g daily. The acetylator phenotype of each subject had been established previously. The serum concentrations of the parent drug and its sulphapyridine-metabolites were determined and the adverse effects were recorded. There was no correlation between the serum concentrations of sulphasalazine and the adverse effects. The slow acetylators obtained enhancement of serum concentrations of sulphapyridine earlier than the rapid acetylators. They also reported adverse effects earlier and of more pronounced nature than the rapid acetylators. The data as a whole suggest that the adverse effects observed were caused by the metabolite sulphapyridine and that they are influenced by the polymorphic acetylation.Sulphasalazine (salicyl-azo-sulphapyridine) was first used in the treatment of ulcerative colitis by Svartz (1942). Controlled studies have demonstrated the clinical efficacy of the drug in mild and moderate cases of ulcerative colitis (Baron, Connell, LennardJones, and Avery Jones, 1962;Dick, Grayson, Carpenter, and Petrie, 1964). It has also been shown that the relapse rate is reduced upon sulphasalazine therapy (Misiewicz, Lennard-Jones, Connell, Baron, and Avery Jones, 1965). The use of the drug is, however, somewhat marred by adverse effects such as nausea, headache, abdominal discomfort, and malaise (

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…One study supports this supposition (Kumagai et al, 2004), whereas others do not (Azad Khan et al, 1980;Pullar et al, 1985;Bax et al, 1986;Kitas et al, 1992;Ricart et al, 2002). Slow acetylator status does seem to PHARMACOGENETICS, DRUG METABOLISM, AND CLINICAL PRACTICE increase the risk of side effects (Schroder and Price Evans, 1972;Azad Khan et al, 1980;Pullar et al, 1985;Rahav et al, 1990;Laversuch et al, 1995;Gunnarsson et al, 1997;Tanaka et al, 2002;Ohtani et al, 2003), although this risk has not been observed in all studies (Chalmers et al, 1990;Kitas et al, 1992;Wadelius et al, 2000;Ricart et al, 2002;Kumagai et al, 2004). It is reasonable to expect that slow acetylators might experience more problems with sulfasalazine given that a number of the side effects (e.g., nausea and vomiting) are associated with elevated sulfapyridine concentrations (Das et al, 1973;Rahav et al, 1990).…”

“…Sulfapyridine is essentially completely absorbed and is responsible for the antirheumatic effects of this drug. NAT2 acetylates sulfapyridine (Das and Eastwood, 1975) with average plasma concentrations ϳ2-fold higher and half-life ϳ3-fold longer in slow acetylators (with considerable overlap) (Schroder and Price Evans, 1972;Azad Khan et al, 1983). Thus, it could be anticipated that the efficacy of this drug in rheumatoid arthritis would vary with acetylator status.…”

The metabolism of salicylazosulphapyridine in ulcerative colitis: I The relationship between metabolites and the response to treatment in inpatients

“…Though the degree of absorption and excretion of SASP as the parent drug was in the same range as in healthy volunteers, the absorption and urinary excretion of the metabolites of SP were lower than found in the volunteers (80 % of the dose). However, in a short study in healthy persons (one to five days) in England a comparatively smaller excretion (about 60% of the dose) of SP and its metabolites was noted (Schroder and Evans, 1972a). The SASP serum concentration reaches a peak level within three to five hours after ingestion.…”

N-Acetyltransferase 2 Genotype-Related Sulfapyridine Acetylation and Its Adverse Events.

“…Adverse events such as nausea, vomiting, headache, malaise, hemolytic anaemia and reticulocytosis appear to be dependent on the serum SP concentration. [4][5][6][7][8] In contrast, a hypersensitivity reaction or those often found in an idiosyncratic manner at the initiation of therapy are independent of SASP dose, including skin rashes, aplastic anaemia, and hepatic and pulmonary dysfunction.7,9) NAT2 activity has been diagnosed by phenotyping; that is, examining plasma concentrations or urinary excretion profiles of tentatively administered test drugs, including isoniazid, caffeine and sulfamethazine (sulfadimidine), and the patients have been stratified into rapid, intermediate and slow acetylators. Based on the finding that adverse events after SASP administration have occurred more frequently with a slow acetylator than a rapid acetylator, dose individualization has been carried out according to NAT2 activity diagnosis by phenotyping to minimize the adverse events.…”