Development of a Prodrug of Salicylic Acid, Salicylic Acid-l-alanine Conjugate, Utilizing Hydrolysis by Rabbit Intestinal Microorganisms

Abstract

The hydrolysis of salicylic acid-L-alanine conjugate (salicyl-L-alanine) following oral, intravenous, intracaecal and rectal administration (60, 10, 5 and 5 mg kg-1, respectively: salicylic acid equivalent) was examined in rabbits. Salicylic acid was detected in the blood 2 h after oral administration of salicyl-L-alanine and reached a maximum concentration at 10 h, whereas salicyl-L-alanine was rapidly eliminated. In contrast, unchanged salicyl-L-alanine only was found following intravenous administration of salicyl-L-alanine, suggesting that presystemic de-conjugation of salicyl-L-alanine was involved. The intestinal mucosal de-conjugation of salicyl-L-alanine was not recognized in the in-situ intestinal sac preparation with complete mesenteric venous blood collection. Immediate and very extensive salicylic acid formation in the caecum was found following intracaecal administration of salicyl-L-alanine. After oral pretreatment of rabbits with kanamycin sulphate, a significant inhibition of salicylic acid formation following intracaecal administration of salicyl-L-alanine was observed, indicating that the intestinal microorganisms were responsible for the biotransformation of salicyl-L-alanine. In-vitro incubation of salicyl-L-alanine with gut contents showed that the major source of its hydrolysis was the hind gut. Consequently, the blood concentration of salicylic acid was prolonged extensively following rectal administration of salicyl-L-alanine, suggesting the usefulness of salicyl-L-alanine as a prodrug of salicylic acid.

A Novel Prodrug of Salicylic Acid, Salicylic Acid-glycylglycine Conjugate, Utilizing the Hydrolysis in Rabbit Intestinal Microorganisms

“…A small amount of salicyl-glycylglycine was detected in the blood, suggesting that salicyl-glycylglycine itself was poorly absorbed from the stomach and small intestine. The AUC value (0-30 h) for salicyl-glycylglycine was about one-fourth of that for salicyl-L-alanine (850.0 vs 3720.5 pg mL-I min) (Nakamura et al 1992). The apparent partition coefficient of salicyl-glycylglycine (0.05) was relatively low.…”

“…On the other hand, salicylic acid was detected at 2 h after the dose and reached a peak blood concentration (55.6 pg mL-I) at 15 h. The blood concentration of salicylic acid remained above 13.3 pg mL-I, 36 h after the administration of the dose. The AUC value (0-30 h) for salicylic acid, calculated from the blood Concentration profile following oral administration of salicyl-glycylglycine, was about 3-fold that of salicyl-L-alanine (55720.6 vs 19933.0 pg mL-' min) (Nakamura et al 1992).…”

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“…On the other hand, the km value was the largest for S-Glygly, as expected from the high hydrolytic activity of cecal contents against SGlygly to SA measured in vitro (1)(2)(3)(4). Because prodrug hydrolysis to SA was inhibited in rabbits pretreated with kanamycin sulfate, the intestinal microorganisms were thought to accord for the biotransformation of these prodrugs (1,2,10).…”

“…Pharmaceutical Research, 11 (1), [160][161][162][163][164][165][166][167][168][169][170][171][172][173][174]1994 …”