Ahmed S, Imai T, Yoshigae Y, Otagiri M
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Life Sci. 1997;61(19):1879-87. doi: 10.1016/s0024-3205(97)00827-8.
Cutaneous stereoselective hydrolyses of ten ester prodrugs of propranolol in hairless mouse were compared to those in liver and plasma. On the basis of protein content, the hydrolysis rate was greatest with liver homogenate followed by plasma and skin homogenate. The buffer showed the slowest and non-stereoselective hydrolysis. However, skin showed very high stereoselectivity (R/S ratio: 6.7-18.4) as compared with liver (0.7-2.0) and plasma (1.7-4.7). The microsomal esterase activity was higher than cytosolic esterase in liver, while an opposite relation was observed in skin. The smaller Km and larger Vmax values of the (R) isomer than those of the (S) isomer of caproyl- and/or butyryl-propranolol were found in skin and plasma, while Km was the same between (R) and (S) isomers in liver. Enzyme inhibition studies indicated that the carboxylesterases were primarily involved in prodrug hydrolysis in liver. On the other hand, skin and plasma were found to be rich in both carboxylesterases and cholinesterases. Interestingly, the (R) isomer was more sensitive towards butylcholinesterase in skin and plasma, while (S) isomer was more sensitive towards carboxylesterase in plasma. Moreover, no stereoselective inhibition was observed in liver. These data indicated that the hydrolyzing nature of skin esterases responsible for propranolol prodrug was sensitive against stereochemical configuration and more similar to those in plasma esterases than liver esterases.
在无毛小鼠中，将普萘洛尔的十种酯前药的皮肤立体选择性水解与肝脏和血浆中的水解进行了比较。基于蛋白质含量，肝脏匀浆的水解速率最高，其次是血浆和皮肤匀浆。缓冲液的水解速率最慢且无立体选择性。然而，与肝脏（0.7 - 2.0）和血浆（1.7 - 4.7）相比，皮肤表现出非常高的立体选择性（R/S比值：6.7 - 18.4）。肝脏中的微粒体酯酶活性高于胞质酯酶，而在皮肤中观察到相反的关系。在皮肤和血浆中，己酰基 - 和/或丁酰基 - 普萘洛尔的（R）异构体的Km值小于（S）异构体，Vmax值大于（S）异构体，而在肝脏中（R）和（S）异构体之间的Km相同。酶抑制研究表明，羧酸酯酶主要参与肝脏中前药的水解。另一方面，发现皮肤和血浆中羧酸酯酶和胆碱酯酶都很丰富。有趣的是，（R）异构体在皮肤和血浆中对丁酰胆碱酯酶更敏感，而（S）异构体在血浆中对羧酸酯酶更敏感。此外，在肝脏中未观察到立体选择性抑制。这些数据表明，负责普萘洛尔前药水解的皮肤酯酶的水解性质对立体化学构型敏感，并且比肝脏酯酶更类似于血浆酯酶。
