Yoshigae Y, Imai T, Aso T, Otagiri M
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Life Sci. 1998;62(14):1231-41. doi: 10.1016/s0024-3205(98)00053-8.
The bioavailability of propranolol (PL) after oral administration of ester-type prodrug was compared in rat and dog, and the possible reason for species difference was investigated. In dog, the oral bioavailability of PL was enhanced by the use of prodrug due to saturation of metabolism of PL. In contrast, high (10 mg/kg) and low (2.5 mg/kg) doses of butyryl PL and isovaleryl PL failed to improve oral bioavailability of PL in rats. The hydrolase activities for prodrugs in rat liver were lower than those of dog (by 4-12-fold), but those of rat intestinal mucosa were significantly higher than those of dog (50-260-fold). Although it is clear from the in vitro hydrolysis using subcellular fractions that the rapid hydrolysis in intestinal mucosa was mainly due to cytosolic components, the brush-border membrane vesicle in rat intestine also showed hydrolase activity for both prodrugs. In situ absorption experiment in rat revealed an improvement in the apparent absorption rate of PL as the result of prodrug use (1.3-fold) and the nearly complete hydrolysis of isovaleryl PL during intestinal absorption, which is a slower hydrolyzed prodrug than butyryl PL in intestinal mucosa and liver. The defects for enhancing oral bioavailability in rats appears to be based on an unsaturation of metabolism for PL, which is derived from a decrease in PL concentration in hepatocytes, owing to rapid hydrolysis of the prodrug in intestinal mucosa and slow hydrolysis of the prodrug in liver. Furthermore, human intestinal mucosa showed a surprisingly high hydrolase activity in microsomes. Therefore, the oral bioavailability of PL after administration of prodrugs might be not significantly improved in human.
比较了酯型前药口服给药后普萘洛尔（PL）在大鼠和犬体内的生物利用度，并研究了种属差异的可能原因。在犬体内，由于PL代谢饱和，前药的使用提高了PL的口服生物利用度。相比之下，高剂量（10mg/kg）和低剂量（2.5mg/kg）的丁酰PL和异戊酰PL均未能提高大鼠体内PL的口服生物利用度。大鼠肝脏中前药的水解酶活性低于犬（低4-12倍），但大鼠肠黏膜的水解酶活性显著高于犬（高50-260倍）。尽管从使用亚细胞组分的体外水解实验中可以清楚地看出，肠黏膜中的快速水解主要归因于胞质成分，但大鼠肠道的刷状缘膜囊泡对两种前药也表现出水解酶活性。大鼠的原位吸收实验表明，使用前药后PL的表观吸收率有所提高（1.3倍），并且在肠道吸收过程中异戊酰PL几乎完全水解，异戊酰PL在肠黏膜和肝脏中的水解速度比丁酰PL慢。大鼠口服生物利用度提高存在缺陷，似乎是由于PL代谢不饱和，这源于肠黏膜中前药快速水解以及肝脏中前药水解缓慢导致肝细胞内PL浓度降低。此外，人肠黏膜微粒体显示出惊人的高水解酶活性。因此，前药给药后PL在人体内的口服生物利用度可能不会显著提高。
