In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: Pitfalls and promises
In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: Pitfalls and promises
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DOI：
10.1016/j.bcp.2005.12.019
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发表时间：
2006-05-28
影响因子：
5.8
通讯作者：
Mackenzie, PI
中科院分区：
文献类型：
--
作者：
Miners, JO;Knights, KM;Mackenzie, PI
UDP-葡萄糖醛酸基转移酶（UGT）超家族的酶负责许多药物、环境化学品和内源性化合物的代谢。参与给定化合物代谢的UGT的鉴别（反应表型分析）目前依赖于多种确证方法，这些方法可能受到UGT活性对酶源、孵育条件和非典型葡萄糖醛酸化动力学发生的依赖性的混淆。然而，个体UGT的底物和抑制剂“探针”的可用性不断增加，为使用人肝微粒体或肝细胞进行葡萄糖醛酸化反应的可靠表型分析提供了前景，从而提供了与人体药物代谢直接相关的数据。虽然UGT底物选择性的计算预测的可行性已被证明，易于解释和概括的模型的发展需要进一步改进的数据集可用于分析。基于体外动力学数据定量预测葡萄糖醛酸化药物的肝脏清除率和抑制相互作用的大小更成问题。使用人肝微粒体生成的固有清除率（克林特）值低于体内肝清除率，通常为一个数量级。葡萄糖醛酸化药物的体内清除率通常也被人肝细胞的克林特值低估，但程度低于微粒体模型的观察结果。虽然预计系统分析预测不足的潜在原因可能会提供更可靠的体外-体内缩放策略，但体外-体内相关性的机制解释更广泛地等待我们对UGT活性的结构和细胞决定因素的进一步理解。(c)2006年爱思唯尔公司All rights reserved.
Enzymes of the, UDP-glucuronosyltransferase (UGT) superfamily are responsible for the metabolism of many drugs, environmental chemicals and endogenous compounds. Identification of the UGT(s) involved in the metabolism of a given compound (reaction phenotyping') currently relies on multiple confirmatory approaches, which maybe confounded by the dependence of UGT activity on enzyme source, incubation conditions, and the occurrence of atypical glucuronidation kinetics. However, the increasing availability of substrate and inhibitor 'probes' for the individual UGTs provides the prospect for reliable phenotyping of glucuronidation reactions using human liver microsomes or hepatocytes, thereby providing data directly relevant to drug metabolism in humans. While the feasibility of computational prediction of UGT substrate selectivity has been demonstrated, the development of easily interpretable and generalisable models requires further improvement in the datasets available for analysis. Quantitative prediction of the hepatic clearance of glucuronidated drugs and the magnitude of inhibitory interactions based on in vitro kinetic data is more problematic. Intrinsic clearance (CLint) values generated using human liver microsomes under-predict in vivo hepatic clearance, typically by an order of magnitude. In vivo clearances of glucuronidated drugs are also generally under-predicted by CLint values from human hepatocytes, but to a lesser extent than observed with the microsomal model. While it is anticipated that systematic analysis of the potential causes of under-prediction may provide more reliable in vitro-in vivo scaling strategies, mechanistic interpretation of in vitro-in vivo correlation more broadly awaits further advances in our understanding of the structural and cellular determinants of UGT activity. (c) 2006 Elsevier Inc. All rights reserved.