al-Habet S M, Lee H J
Center for Anti-inflammatory Research, College of Pharmacy, Florida A&M University, Tallahassee 32307.
J Pharm Sci. 1990 Oct;79(10):916-8. doi: 10.1002/jps.2600791015.
The in vitro hydrolysis of two new classes of steroid acid esters synthesized from prednisolone as local anti-inflammatory steroids was investigated in rat, rabbit, and human plasma. One class was synthesized by incorporating methoxycarbonyl groups at the 16 position of prednisolone to produce 16 alpha-methoxycarbonyl prednisolone (P16CM) and its 17-deoxy analogue (DP16CM). The other class was synthesized by modifying the ketol side chain of prednisolone to produce methyl 20 alpha- and methyl beta-dihydroprednisolonate (P4 alpha and P4 beta). The P16CM and P4 beta were rapidly and completely hydrolyzed within 1 h of incubation in rat and rabbit plasma and within 4 h in human plasma. There was a marked species difference in the hydrolysis of DP16CM which occurred in the following order: rat greater than human greater than rabbit. The in vitro hydrolysis of P4 alpha was much slower than that of P4 beta; the process continued over 24 h in rat plasma. As expected, no change in the initial concentration of prednisolone was found over 120 h of incubation in rat plasma. This marked species difference in the hydrolysis of these steroid acid esters is probably related to the differences in the amounts, types, and activities of the hydrolyzing enzymes (e.g., esterases) in the plasma of the three species. From this study it can be concluded that the existence of an hydroxyl group at C-17 and the orientation of hydroxyl groups at C-20 play an important role in the systemic hydrolysis rate of the carboxy ester group on the steroid nucleus.
研究了两种由泼尼松龙合成的新型甾体酸酯作为局部抗炎甾体在大鼠、兔和人血浆中的体外水解情况。一类是通过在泼尼松龙的16位引入甲氧基羰基基团合成16α-甲氧基羰基泼尼松龙（P16CM）及其17-脱氧类似物（DP16CM）。另一类是通过修饰泼尼松龙的酮醇侧链合成20α-甲基二氢泼尼松龙甲酯和β-甲基二氢泼尼松龙甲酯（P4α和P4β）。P16CM和P4β在大鼠和兔血浆中孵育1小时内迅速且完全水解，在人血浆中4小时内完全水解。DP16CM的水解存在明显的种属差异，水解顺序如下：大鼠＞人＞兔。P4α的体外水解比P4β慢得多；在大鼠血浆中该过程持续超过24小时。正如预期的那样，在大鼠血浆中孵育120小时内泼尼松龙的初始浓度没有变化。这些甾体酸酯水解的明显种属差异可能与这三种动物血浆中水解酶（如酯酶）的数量、类型和活性差异有关。从这项研究可以得出结论，C-17位羟基的存在以及C-20位羟基的取向对甾体核上羧酸酯基团的全身水解速率起着重要作用。
