Fung Eliza N, Zheng Naiyu, Arnold Mark E, Zeng Jianing
Department of Bioanalytical Sciences, Bristol-Myers Squibb Co., Route 206/Province Line Road, Princeton, NJ 08540, USA.
Bioanalysis. 2010 Apr;2(4):733-43. doi: 10.4155/bio.10.30.
Analysis of prodrugs, with their short half-lives, especially ester-containing ones, poses a unique challenge in developing and validating bioanalytical assays for nonclinical and clinical studies. A screening approach is needed to expeditiously select esterase inhibitors for stabilizing them during sample collection and processing.
The screening process consisted of three steps. Initially, nine different esterase inhibitors were screened at three different plasma concentrations against an ester prodrug. Four inhibitors were chosen for the next step, in which plasma pH and processing temperature were optimized. Finally, whole-blood stability of the prodrug was evaluated. Three inhibitors with optimized plasma pH and processing temperature were selected for further bioanalytical assay development.
An effective approach was successfully developed to promptly select suitable esterase inhibitors for stabilizing ester-containing prodrugs.
前药，尤其是含酯前药，半衰期较短，这在为非临床和临床研究开发和验证生物分析方法时带来了独特挑战。需要一种筛选方法来快速选择酯酶抑制剂，以便在样品采集和处理过程中稳定它们。
筛选过程包括三个步骤。首先，针对一种酯前药，在三种不同的血浆浓度下对九种不同的酯酶抑制剂进行筛选。选择了四种抑制剂进入下一步，在这一步中优化血浆pH值和处理温度。最后，评估前药在全血中的稳定性。选择了三种在优化的血浆pH值和处理温度下的抑制剂用于进一步的生物分析方法开发。
成功开发了一种有效的方法，可迅速选择合适的酯酶抑制剂来稳定含酯前药。
