Strategies in the design of solution-stable, water-soluble prodrugs III: influence of the pro-moiety on the bioconversion of 21-esters of corticosteroids.
Strategies in the design of solution-stable, water-soluble prodrugs III: influence of the pro-moiety on the bioconversion of 21-esters of corticosteroids.
复制标题
溶液稳定的水溶性前药设计策略 III：前体部分对皮质类固醇 21-酯生物转化的影响。
DOI：
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发表时间：
1985
期刊：
影响因子：
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通讯作者：
A. Forbes
中科院分区：
文献类型：
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作者：
B. D. Anderson;R. Conradi;C. Spilman;A. Forbes
用作水溶性前药的琥珀酸酯和许多其他羧酸酯由于其水溶液不稳定而用途有限。在早期的研究中，考虑到影响酯水解的各种物理有机因素，制定了一种溶液稳定的皮质类固醇 21-羧酸酯的设计策略。合成了几种甲基强的松龙的21-酯，并监测了它们在水溶液中的稳定性以证明该方法的可行性。在这项研究中，对在 25℃ 下保质期大于或等于 2 年的甲基强的松龙 21-酯的代表性实例的生物转化进行了监测，以评估其作为前药与市售琥珀酸钠酯相比的效用。在人和恒河猴血清中进行的酯水解研究表明，具有阴离子增溶部分（磺酸盐或羧酸盐）的衍生物在血清中不会水解，而具有阳离子（叔氨基）增溶部分的化合物会被血清酯酶快速水解。还在恒河猴中进行了体内药代动力学研究，以比较几种溶液稳定的前药与 21-琥珀酸酯的生物转化率和总体生物利用度。已经鉴定出在25℃下溶液稳定性超过2年、具有更快的生物转化率和等于或高于琥珀酸酯的总体生物利用度的衍生物。相对生物利用度似乎对增溶前体部分的电荷和前体部分链长高度敏感。
Succinate esters and many other carboxylic acid esters utilized as water-soluble prodrugs have limited utility due to their aqueous solution instability. In an earlier study, a strategy for the design of solution-stable 21-carboxylic acid esters of corticosteroids was developed from a consideration of various physical organic factors which influence ester hydrolysis. Several 21-esters of methylprednisolone were synthesized, and their stability in aqueous solution was monitored to demonstrate the feasibility of the approach. In this study, the bioconversion of representative examples of 21-esters of methylprednisolone exhibiting shelf lives of greater than or equal to 2 years at 25 degrees C was monitored to evaluate their utility as prodrugs in comparison to a commercially marketed sodium succinate ester. Ester hydrolysis studies conducted in human and rhesus monkey serum suggest that derivatives having an anionic solubilizing moiety (sulfonate or carboxylate) are not hydrolyzed in serum, while compounds having a cationic (tertiary amino) solubilizing moiety are hydrolyzed rapidly by serum esterases. In vivo pharmacokinetic studies in rhesus monkeys were also conducted to compare the bioconversion rates and overall bioavailability of several solution-stable prodrugs with the 21-succinate ester. Derivatives having solution stability exceeding 2 years at 25 degrees C with a faster bioconversion rate and an overall bioavailability equal to or higher than that of the succinate ester have been identified. Relative bioavailability appears to be highly sensitive to the charge of the solubilizing pro-moiety and pro-moiety chain length.