Synthesis and In Vitro/In Vivo Evaluation of 5‐Aminosalicyl‐Glycine as a Colon‐Specific Prodrug of 5‐Aminosalicylic Acid

Abstract

A simple synthetic route for the preparation of amino acid conjugate of 5‐aminosalicylic acid (5‐ASA) was exploited and prepared 5‐aminosalicyl‐glycine (5‐ASA‐Gly) in good yield. In vitroand in vivo properties of 5‐ASA‐Gly as a colon‐specific prodrug of 5‐ASA were investigated using rats as the test animal. Incubation of 5‐ASA‐Gly with cecal or colonic contents at 37°C released 5‐ASA in 65 or 27% of the dose in 8 h, respectively. No 5‐ASA was detected from the incubation of 5‐ASA‐Gly with the homogenates of stomach or small intestine. Plasma concentration of 5‐ASA‐Gly decreased rapidly after intravenous administration of 5‐ASA‐Gly, and no 5‐ASA was detected in the blood, which indicated 5‐ASA‐Gly was not degraded in the plasma. After oral administration of 5‐ASA‐Gly, about 50% of the administered dose was recovered as 5‐ASA and N‐acetyl‐ASA and 3% as 5‐ASA‐Gly from feces and 14% as 5‐ASA‐Gly and 28% as 5‐ASA and N‐acetyl‐ASA from urine in 24h. These results suggested that a large fraction of 5‐ASA‐Gly was delivered to the large intestine and activated to liberate 5‐ASA. For comparison, total recovery of 5‐ASA and N‐acetyl‐5‐ASA from feces after oral administration of 5‐ASA‐Gly was greater than that from sulfasalazine, which is one of the most commonly prescribed prodrugs of 5‐ASA. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89:594–602, 2000