A polymeric drug for treatment of inflammatory bowel disease.
Sulfasalazine (SASP) consists of salicylic acid azo linked at the 5-position to a pyridine-containing sulfonamide. This drug, currently used in inflammatory bowel disease treatment, is reductively cleaved by anaerobic bacteria in the lower bowel to 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP). Recent reports indicate that 5-ASA is the active therapeutic moiety and that SP is responsible for a variety of adverse clinical side effects. Water-soluble polymer 7, which contains salicylate residues azo linked at the 5-position to an inert polymer backbone, has been synthesized for the site-specific reductive release of 5-ASA in the lower bowel. Preparations of 7 deliver (chemical reduction) greater than 1.96 mmol of 5-ASA/g of polymer. In vitro studies with the polymer in anaerobic rat cecal bacteria demonstrated a reduction rate of approximately 1 mu equiv of azo bond h-1 (mL of cecal content)-1. A pharmacokinetic comparison of polymer and SASP showed similar deliveries of 5-ASA and metabolites to the lower bowel, blood, and urine of orally dosed rats. Polymer 7 proved more active than SASP or 5-ASA in the guinea pig ulcerative colitis model. Potential therapeutic advantages of 7 include nonabsorption/nonmetabolism in the small intestine, direct 5-ASA release at the disease site, and nonabsorption/nonmetabolism of the reduction-released carrier polymer.
D010131:Aminosalicylic Acid / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D006168:Guinea Pigs; D007422:Intestines / Q000382:microbiology; D011108:Polymers / Q000138:chemical synthesis* / Q000627:therapeutic use; D012459:Salicylates / Q000138:chemical synthesis* / Q000627:therapeutic use; D013427:Sulfapyridine / Q000378:metabolism; D012460:Sulfasalazine / Q000378:metabolism / Q000627:therapeutic use
D011108:Polymers; D012459:Salicylates; D012460:Sulfasalazine; D010131:Aminosalicylic Acid; D013427:Sulfapyridine