A novel prodrug of salicylic acid, salicylic acid-glycylglycine conjugate, utilizing the hydrolysis in rabbit intestinal microorganisms.
The hydrolysis of salicylic acid-glycylglycine conjugate (salicyl-glycylglycine) following oral, intravenous, intracaecal and rectal administration (434, 72, 36 and 36 mumol kg-1, respectively: equivalent to salicylic acid) was examined in rabbits to develop a novel prodrug of salicylic acid. Salicylic acid was detected in the blood 2 h after oral administration of salicyl-glycylglycine and it reached a maximum level (55.6 micrograms mL-1) at 15 h, whereas a small amount of salicyl-glycylglycine was found in the blood. In contrast, unchanged salicyl-glycylglycine was found mainly in the blood following its intravenous administration, suggesting the involvement of presystemic deconjugation in the hydrolysis of salicyl-glycylglycine. Immediate and very extensive salicyclic acid formation in the caecum was observed following intracaecal administration of salicyl-glycylglycine, suggesting that the intestinal microorganisms were responsible for the biotransformation of this compound. In-vitro incubation of salicyl-glycylglycine with caecal content showed that salicyl-glycylglycine was hydrolysed efficiently in the caecum. Consequently, the blood concentration of salicylic acid was prolonged extensively following rectal administration of salicyl-glycylglycine, indicating the usefulness of salicyl-glycylglycine as a prodrug of salicylic acid.
Nakamura
J
J
School of Pharmaceutical Sciences, Nagasaki University, Japan.
Asai
K
K
Nishida
K
K
Sasaki
H
H
D000284:Administration, Oral; D000285:Administration, Rectal; D000818:Animals; D001419:Bacteria / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D006868:Hydrolysis; D007275:Injections, Intravenous; D007422:Intestines / Q000382:microbiology*; D008297:Male; D011355:Prodrugs / Q000378:metabolism*; D011817:Rabbits; D012459:Salicylates / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility
D004151:Dipeptides; D011355:Prodrugs; D012459:Salicylates; C078482:salicyl-glycyl-glycine