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首页> 外文期刊>Combinatorial Chemistry & High Throughput Screening >Screening Drugs for Metabolic Stability Using Pulsed Ultrafiltration Mass Spectrometry
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Screening Drugs for Metabolic Stability Using Pulsed Ultrafiltration Mass Spectrometry

机译：脉冲超滤质谱法筛选代谢稳定性药物

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摘要

A pulsed ultrafiltration-mass spectrometric screening method has been developed to evaluate the metabolic stability of drugs. Pooled human liver microsomes containing cytochrome P450 enzymes were trapped by an ultrafiltration membrane in a stirred flow-through chamber, and eight β-blocker drugs including acebutolol, alprenolol, atenolol, metoprolol, oxprenolol, pindolol, propranolol, and timolol were flow-injected through the chamber along with the cofactor NADPH. The ultrafiltrate was collected, concentrated and analyzed by using liquid chromatography-tandem mass spectrometry (LC-MS-MS) in order to quantitate the unmetabolized fraction of each drug. The metabolic stability of each β-blocker was determined based on the difference between the corresponding LC-MS-MS peak areas of an experimental incubation and a control without NADPH. A flow-through incubation method, pulsed ultrafiltration metabolic screening minimizes the potential for product feed back inhibition of cytochrome P450 enzymes. The importance of this phenomenon was illustrated by the observation that the metabolic stability of the set of β-blocker drugs measured using pulsed ultrafiltration more closely resembled the in vivo stability than that determined using a conventional batch incubation with microsomes or an incubation with human hepatocytes. Since a mixture of compounds was analyzed, the relative metabolic stability of each compound could be assessed by comparison to the other compounds in the incubation. This approach might be particularly useful for the ranking of a directed library of drug leads with respect to metabolic stability and then the selection of lead compounds for further drug development.
机译：已经开发了脉冲超滤质谱分析方法来评估药物的代谢稳定性。通过超滤膜将混合的含有细胞色素P450酶的人肝微粒体截留在搅拌过的流通室中，并通过流动注射法将八种β-受体阻滞剂药物（包括醋丁洛尔，阿普洛尔，阿替洛尔，美托洛尔，氧戊烯醇，品多洛尔，普萘洛尔和噻吗洛尔）通过流动注射腔室与辅因子NADPH一起。收集超滤液，浓缩并通过使用液相色谱-串联质谱法（LC-MS-MS）进行分析，以定量每种药物的未代谢级分。根据实验温育的相应LC-MS-MS峰面积与无NADPH的对照之间的差异，确定每种β受体阻滞剂的代谢稳定性。流通式温育方法，脉冲超滤代谢筛选可最大程度地减少细胞色素P450酶产物反馈抑制的可能性。通过观察发现，与使用常规的微粒体分批培养或人肝细胞的培养相比，使用脉冲超滤法测量的一组β-阻滞剂药物的代谢稳定性与体内稳定性更相似，这说明了这种现象的重要性。由于分析了化合物的混合物，因此可以通过与孵育中的其他化合物进行比较来评估每种化合物的相对代谢稳定性。这种方法对于根据代谢稳定性对药物前导的有向文库进行排名，然后选择用于进一步药物开发的前导化合物可能特别有用。

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