Salicylazosulfapyridine in Inflammatory Bowel Disease Kiron M. Das, MD, PhD, and Irmin Sternlieb, MD
Salicylazosulfapyridine (SASP) (Azulfidine, Pharmacia; SAS-500, Rowell Laboratories Inc.) has been available as a therapeutic compound since 1940 when Svartz (1) in collaboration with chemists from Pharmacia Company developed an agent by combining a sulfonamide with salicylic acid intended for the treatment of patients with rheumatoid arthritis. A combination of 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP), through an azo link, was synthesized and used empirically for patients with ulcerative colitis. There were good results in the first 12 patients treated with SASP in 1942 (1). A later series of 124 s i m i l a r patients (2) confirmed the earlier results and indicated that SASP was superior to absorbable and nonabsorbable sulfonamides in the treatment of ulcerative colitis (3-6). Controlled trials established the value of SASP in active colitis (7-10) and its effectiveness in the prevention of relapses of ulcerative colitis during: long-term therapy (11-12), although in one series the prophylactic effect of SASP was found to be doubtful (13). The value of SASP in the management of Crohn's disease, which has not yet been settled (14-19), is being studied in a multicenter controlled trial in North America. SASP has also been used with some success in patients with ulcerative postdysenteric colitis (20) and scleroderma (21). From the Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York. Supported in part by grants from the National Foundation for Ileitis and Colitis and the Philip and Helen Sills Foundation. Address for reprint requests: Dr. K.M. Das, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461. Digestive Diseases, Vol. 20, No. 10 (October 1975)
Although SASP has been used quite extensively during the last two decades, a better understanding of the phai'macokinetics and the relationship between metabolites and response to treatment of this drug has only recently been obtained (22-26). We have learned that only about 10-15~ of an ingested dose is absorbed from the smail bowel as SASP; the remainder reaches the colon where it is split into SP and 5ASA. There, most of the SP is absorbed, whereas the 5-ASA moiety is largely excreted in the stool. About 80% of the ingested drtig is absorbed from these various sites and is ultimately excreted in the urine. There it can be recovered to a minor extent (up to 1 5 % ) a s SASP, but most of it reappears as SP metabolites (Figure 1, Table 1). Absence of the colon affects both metabolism and absorption of the drug resulting in the excretion, witk the ileostomy effluent, of the bulk (about 70%) of the administered dose as SASP, and merely 1007o as free SP (27). Obviously, colonic bacteria play an important role in the splitting of SASP, a~ shown experimentally in studies with conventional and germ-free rats (28). After absorption, most SP is acetylated or acetylated, hydroxylated and glucuronidized, probably in the liver. The relative pro~oortion of acetylation is a function of the genetically determined acetylator phenotype (29). Indeed, acetylation of SP proceeds parallel to that of isoniazid and sulfadimidine (30, 31) and individuals who are rapid acetylators have higher fractions of AcSP than SP in serum and urine. Several mechanisms of action of SASP have been suggested. A particular affinity of the drug for colonic connective tissue and serosal membrane was originally postulated by Svartz (1) 971
DAS & S T E R N L I E B
BLOOD SASP FREE SP ............
P (UP TO 10%) f, ITS METABOLITES (60%) 5-ASA (20~176 SP (25%) 5-ASA (80%)
STOOL Fig 1. Schema showing the absorption, metabolism, and excretion of salicylazosulfapyridine. The figures in parentheses indicate the average values in terms of percentage of the administered dose.
and was recently proven for SASP and 5-ASA (but not for SP) with the aid of autoradiographic techniques (32). Evidently such an affinity would have to be mediated via the mucosa because only about 15% of the ingested SASP is 972
available systemically (27). Another possibility is that the major pharmacologically active component of SASP is SP and that, consequently, the compound SASP may merely act as a vehicle for the active metabolite to the site of inDigestive Diseases, Vol. 20, No. 10 (October 1975)
SASP IN INFLAMMATORY BOWEL DISEASE Table 1. Mean Steady-State Serum Concentrations and 24-Hr Urinary Excretions of SASP and Its Metabolites in Normal Subjects and Patients Serum (/~g/ml) Reference Normal controls Ulcerative colitis* Ulcerative colitis1Crohn's colitis Crohn's ileocolitis (unoperated) Patients with ileostomy Patients with colostomy
Urine (% administered dose)
(23) (25) (25) (22)
8 18 10 7
33 44 5 38