Colon-specific prodrugs of 5-aminosalicylic acid: synthesis and in vitro/in vivo properties of acidic amino acid derivatives of 5-aminosalicylic acid.
5-aminosalicyl-L-aspartic acid (5-ASA-Asp) and 5-aminosalicyl-L-glutamic acid (5-ASA-Glu) were synthesized and their properties as colon-specific prodrugs of 5-aminosalicylic acid (5-ASA) were investigated employing rats as test animals. Incubation of 5-ASA-Asp and 5-ASA-Glu with the homogenates of tissue and contents of stomach or small intestine released no 5-ASA, indicating that they were stable in this condition. Incubation of 5-ASA-Asp with the cecal contents released 5-ASA 37%, whereas 5-ASA-Glu released only 8% of the dose in 16 h. Plasma concentration of 5-ASA-Asp after intravenous administration decreased rapidly and became undetectable in 60 min. No 5-ASA was detected in the blood, which indicated 5-ASA-Asp was stable in the plasma. After oral administration of 5-ASA-Asp, concentration of 5-ASA, its metabolite N-acetyl-5-ASA, and 5-ASA-Asp in the plasma, feces, and urine was determined. In the plasma, 5-ASA-Asp was not detected and the concentration of 5-ASA or N-acetyl-5-ASA was very low. About 33% of the administered dose was recovered as 5-ASA and N-acetyl-5-ASA and 43% as 5-ASA-Asp from feces, and 20% as 5-ASA and N-acetyl-5-ASA and 1% as 5-ASA-Asp from urine in 24 h. These results suggested that most of 5-ASA-Asp was delivered to the large intestine and about half of the administered dose was activated to liberate 5-ASA. After oral administration of free 5-ASA, fecal recovery was only 7% of the dose in 24 h and more than 80% was recovered from urine. Comparing 5-ASA-Asp and free 5-ASA, the amount of 5-ASA available in the large intestine was much larger, while the amount of 5-ASA in urine, which might be related to the systemic toxicity of 5-ASA, was much lower by the administration of 5-ASA-Asp than free 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; D024342:Amino Acids, Acidic / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000652:urine; D003106:Colon / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005753:Gastric Mucosa / Q000378:metabolism; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D019804:Mesalamine / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000652:urine; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D024342:Amino Acids, Acidic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; D019804:Mesalamine