To elucidate the role of the small bowel and liver in sulfasalazine (SASP) metabolism, we performed studies in patients, cats, and rats. The role of the small bowel in absorption and metabolism of SASP was determined by the amount of administered SASP excreted in ileostomy effluents, and the concentration of serum and urinary SASP and its metabolites, sulfapyridine and 5-amino salicylic acid. Seventy-five to ninety percent of the drug was excreted in ileostomy effluents of 6 patients as SASP, and only 5% of the dose was sulfapyridine. In cats, ileostomy and portal venous cannulations revealed that 20-30% of administered SASP is absorbed from the small bowel without being metabolized. The role of the liver in SASP metabolism was established in vivo and in vitro. SASP metabolites were measured in bile, serum, and urine of 2 patients with a choledochal T-tube and in serum and bile in six cats and four rats. Twenty to fifty percent of the absorbed drug was excreted in bile as SASP and no detectable sulfapyridine appeared in the bile. SASP concentration in peripheral blood and urine ranged between 3 and 12 μg/ml, and no significant amount of sulfapyridine metabolites were detected in the bile, serum, or urine of animals with an ileostomy. In vitro experiments with liver from cats and rats showed nearly complete reduction of SASP into metabolites. These studies reveal that SASP is not metabolized by the liver in vivo, and after absorption from the small bowel, 25-50% of the SASP is excreted unchanged in the bile, and the rest enters the circulation. Implications of these results in the treatment of patients with Crohn's disease of the small intestine are discussed.
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