Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance.
Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance.
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DOI：
10.1208/s12248-016-9962-6
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发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Marathe PH
中科院分区：
文献类型：
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作者：
Argikar UA;Potter PM;Hutzler JM;Marathe PH
多年来，在减少由于细胞色素P450介导的氧化引起的代谢不稳定性方面取得了重大进展。高通量代谢稳定性筛选已经使得具有很少或没有氧化代谢的化合物的发展成为可能。此外，目前追求的化学型的高亲脂性和低水溶性降低了肾排泄的可能性。因此，这些低微粒体转换化合物通常是非CYP介导的代谢的底物。UGT、酯酶和醛氧化酶是参与催化这种代谢的主要酶。肝细胞提供了一个很好的工具，以确定这些途径，包括阐明主要代谢产物。为了预测P450介导的代谢的人体PK参数，已积极研究了使用肝微粒体、肝细胞和肠微粒体的体外-体内外推。然而，这些方法尚未对非P450酶进行充分评估。除了肝脏的参与，肝外酶（肠，肾，肺）也可能有助于这些途径。虽然在预测主要由肝脏介导的代谢途径和清除率方面取得了相当大的进展，但在表征肝外代谢和预测清除率方面的进展缓慢。尚没有充分表征的体外系统或体内动物模型来评估药物间相互作用的可能性和多态性引起的受试者间变异性。在这里，我们专注于适当的体外研究，以表征非CYP介导的代谢的效用;了解所涉及的酶，然后在适当表征的替代种属中进行药代动力学研究。该综述将突出在建立体外-体内相关性方面取得的进展;预测人体清除率，并避免非β-内酰胺酶介导的代谢途径占主导地位时昂贵的临床失败。
Over the years, significant progress has been made in reducing metabolic instability due to cytochrome P450-mediated oxidation. High throughput metabolic stability screening has enabled advancement of compounds with little to no oxidative metabolism. Furthermore, high lipophilicity and low aqueous solubility of presently pursued chemotypes reduces the probability of renal excretion. As such, these low microsomal turnover compounds are often substrates for non CYP-mediated metabolism. UGTs, esterases and aldehyde oxidase are major enzymes involved in catalyzing such metabolism. Hepatocytes provide an excellent tool to identify such pathways including elucidation of major metabolites. To predict human PK parameters for P450-mediated metabolism, in vitro–in vivo extrapolation using hepatic microsomes, hepatocytes, and intestinal microsomes has been actively investigated. However, such methods have not been sufficiently evaluated for non-P450 enzymes. In addition to the involvement of liver, extra-hepatic enzymes (intestine, kidney, lung) are also likely to contribute to these pathways. While there has been considerable progress in predicting metabolic pathways and clearance primarily mediated by the liver, progress in characterizing extra-hepatic metabolism and prediction of clearance has been slow. Well-characterized in vitro systems or in vivo animal models to assess drug-drug interaction potential and inter-subject variability due to polymorphism are not available. Here we focus on the utility of appropriate in vitro studies to characterize non CYP-mediated metabolism; understand the enzymes involved followed by pharmacokinetic studies in the appropriately characterized surrogate species. The review will highlight progress made in establishing in vitro-in vivo correlation; predicting human clearance and avoid costly clinical failures when non-CYP mediated metabolic pathways are predominant.