Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer Global R&D, Groton, Connecticut 06340, USA.
Toxicol Sci. 2012 Mar;126(1):114-27. doi: 10.1093/toxsci/kfr339. Epub 2011 Dec 13.
Safety attrition of drugs during preclinical development as well as in late-stage clinical trials continues to be a challenge for the pharmaceutical industry for patient welfare and financial reasons. Hepatic, cardiac, and nephrotoxicity remain the main reasons for compound termination. In recent years, efforts have been made to identify such liabilities earlier in the drug development process, through utilization of in silico and cytotoxicity models. Several publications have aimed to predict specific organ toxicities. For example, two large-scale evaluations of hepatotoxic compounds have been conducted. In contrast, only small cardiotoxic and nephrotoxic compound sets have been evaluated. Here, we investigated the utility of hepatic-, cardiac-, and kidney-derived cell lines to (1) accurately predict cytotoxicity and (2) to accurately predict specific organ toxicities. We tested 273 hepatotoxic, 191 cardiotoxic, and 85 nephrotoxic compounds in HepG2 (hepatocellular carcinoma), H9c2 (embryonic myocardium), and NRK-52E (kidney proximal tubule) cells for their cytotoxicity. We found that the majority of compounds, regardless of their designated organ toxicities, had similar effects in all three cell lines. Only approximately 5% of compounds showed differential toxicity responses in the cell lines with no obvious correlation to the known in vivo organ toxicity. Our results suggest that from a general screening perspective, different cell lines have relatively equal value in assessing general cytotoxicity and that specific organ toxicity cannot be accurately predicted using such a simple approach. Select organ toxicity potentially results from compound accumulation in a particular tissue, cell types within organs, metabolism, and off-target effects. Our analysis, however, demonstrates that the prediction can be improved significantly when human C(max) values are incorporated.
由于患者福利和经济原因，药物在临床前开发和后期临床试验中的安全性损失仍然是制药行业面临的挑战。肝、心和肾毒性仍然是化合物终止的主要原因。近年来，人们努力通过利用计算机和细胞毒性模型，在药物开发过程的早期识别这些风险。已经有几项研究旨在预测特定器官毒性。例如，已经进行了两项大规模的肝毒性化合物评估。相比之下，只有少量的心脏毒性和肾脏毒性化合物进行了评估。在这里，我们研究了肝、心和肾来源的细胞系在以下两个方面的应用：（1）准确预测细胞毒性，（2）准确预测特定的器官毒性。我们在 HepG2（肝细胞癌）、H9c2（胚胎心肌）和 NRK-52E（肾近端小管）细胞中测试了 273 种肝毒性、191 种心脏毒性和 85 种肾毒性化合物的细胞毒性。我们发现，大多数化合物，无论其指定的器官毒性如何，在这三种细胞系中都有相似的作用。只有大约 5%的化合物在细胞系中表现出不同的毒性反应，与已知的体内器官毒性没有明显的相关性。我们的结果表明，从一般筛选的角度来看，不同的细胞系在评估一般细胞毒性方面具有相对相等的价值，并且不能通过这种简单的方法准确预测特定的器官毒性。特定的器官毒性可能是由于化合物在特定组织、器官内的细胞类型、代谢和脱靶效应中的积累所致。然而，我们的分析表明，当纳入人体 C（max）值时，预测可以显著提高。
