Synthesis and in vitro/in vivo evaluation of 5-aminosalicyl-glycine as a colon-specific prodrug of 5-aminosalicylic acid.
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 vitro and 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 degrees 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 24 h. 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.
Jung
Y J
YJ
College of Pharmacy, Pusan National University, Pusan 609-735, Korea.
Lee
J S
JS
Kim
Y M
YM
D000284:Administration, Oral; D000636:Aminosalicylic Acids / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D003106:Colon / Q000378:metabolism*; D004064:Digestive System / Q000378:metabolism; D004355:Drug Stability; D005243:Feces / Q000737:chemistry; D006626:Hippurates / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D008297:Male; D019804:Mesalamine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012460:Sulfasalazine / Q000493:pharmacokinetics / Q000652:urine
C116885:5-aminosalicyl-glycine; D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D006626:Hippurates; D011355:Prodrugs; D012460:Sulfasalazine; D019804:Mesalamine