Takahashi K, Tamagawa S, Sakano H, Katagi T, Mizuno N
Faculty of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan.
Biol Pharm Bull. 1995 Oct;18(10):1401-4. doi: 10.1248/bpb.18.1401.
The stereochemical characteristics of the hydrolysis of several ester-type prodrugs of propranolol, O-acetyl, O-propionyl, O-butyryl, O-pivaloyl and succinyl esters, were studied in phosphate buffer (pH 7.4), rat plasma and rat tissue homogenates. In phosphate buffer, no differences were observed in the hydrolysis rate between the esters of (R)- and (S)-propranolol. The effects of the ester moieties on the hydrolysis rate in phosphate buffer were in the following order: acetate > propionate > butyrate > succinate > pivalate. In rat plasma and tissue homogenates, the hydrolysis of the esters was accelerated, and stereoselective hydrolysis was observed. In plasma, the hydrolysis of the (R)-isomer was faster than that of the (S)-isomer except for the succinate ester. On the other hand, in the liver and intestine homogenates, the (S)-isomer was hydrolyzed faster than the (R)-isomer except for the succinate and pivalate esters in the liver homogenate. Also, the ratio of the hydrolysis rates (S/R) changed with the type of prodrug. As the length of the alkyl chain of the ester increased, the S/R ratio approached unity in liver and intestine homogenates but stayed almost constant in plasma. For the pivalate ester, stereoselective hydrolysis was observed in plasma and intestine homogenate but not in liver homogenate. The stereoselective hydrolysis of the succinate ester was observed only in intestine homogenate, but the S/R ratio was almost 1 in plasma, liver and intestine homogenates. No interconversion between (R)- and (S)-isomer was observed during the hydrolysis of any of the ester prodrugs. These results indicate that hydrolysis of ester-type prodrugs of propranolol occurs stereoselectively in rat tissues, and that its selectivity is dependent on the kind of tissue and prodrug.
研究了普萘洛尔几种酯型前药（O-乙酰酯、O-丙酰酯、O-丁酰酯、O-新戊酰酯和琥珀酸酯）在磷酸盐缓冲液（pH 7.4）、大鼠血浆和大鼠组织匀浆中的水解立体化学特征。在磷酸盐缓冲液中，(R)-和(S)-普萘洛尔酯的水解速率未观察到差异。酯基对磷酸盐缓冲液中水解速率的影响顺序为：乙酸酯＞丙酸酯＞丁酸酯＞琥珀酸酯＞新戊酸酯。在大鼠血浆和组织匀浆中，酯的水解加速，并观察到立体选择性水解。在血浆中，除琥珀酸酯外，(R)-异构体的水解速度比(S)-异构体快。另一方面，在肝脏和肠道匀浆中，除肝脏匀浆中的琥珀酸酯和新戊酸酯外，(S)-异构体的水解速度比(R)-异构体快。此外，水解速率之比（S/R）随前药类型而变化。随着酯烷基链长度的增加，肝脏和肠道匀浆中的S/R比接近1，但在血浆中几乎保持不变。对于新戊酸酯，在血浆和肠道匀浆中观察到立体选择性水解，但在肝脏匀浆中未观察到。仅在肠道匀浆中观察到琥珀酸酯的立体选择性水解，但在血浆、肝脏和肠道匀浆中S/R比几乎为1。在任何酯前药水解过程中均未观察到(R)-和(S)-异构体之间的相互转化。这些结果表明，普萘洛尔酯型前药在大鼠组织中发生立体选择性水解，其选择性取决于组织类型和前药类型。
