Nakamura J, Asai K, Nishida K, Sasaki H
School of Pharmaceutical Sciences, Nagasaki University, Japan.
J Pharm Pharmacol. 1992 Sep;44(9):713-6. doi: 10.1111/j.2042-7158.1992.tb05505.x.
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.
为开发一种新型水杨酸前药，在兔体内研究了口服、静脉注射、盲肠内注射和直肠给药（分别为434、72、36和36 μmol kg⁻¹：相当于水杨酸）后水杨酸 - 甘氨酰甘氨酸共轭物（水杨酰 - 甘氨酰甘氨酸）的水解情况。口服水杨酰 - 甘氨酰甘氨酸后2小时在血液中检测到水杨酸，15小时达到最高水平（55.6 μg mL⁻¹），而血液中发现少量水杨酰 - 甘氨酰甘氨酸。相反，静脉注射后血液中主要发现未变化的水杨酰 - 甘氨酰甘氨酸，这表明首过去共轭作用参与了水杨酰 - 甘氨酰甘氨酸的水解。盲肠内注射水杨酰 - 甘氨酰甘氨酸后，在盲肠中立即观察到大量水杨酸生成，表明肠道微生物负责该化合物的生物转化。水杨酰 - 甘氨酰甘氨酸与盲肠内容物的体外孵育表明，水杨酰 - 甘氨酰甘氨酸在盲肠中被有效水解。因此，直肠给药水杨酰 - 甘氨酰甘氨酸后，水杨酸的血药浓度显著延长，表明水杨酰 - 甘氨酰甘氨酸作为水杨酸前药的有效性。
