Display Settings:

Format

Send to:

Choose Destination
We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Toxicol Sci. 2012 Mar;126(1):114-27. doi: 10.1093/toxsci/kfr339. Epub 2011 Dec 13.

Evaluation of drugs with specific organ toxicities in organ-specific cell lines.

Author information

  • 1Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer Global R&D, Groton, Connecticut 06340, USA.

Abstract

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.

PMID:
22166485
[PubMed - indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Write to the Help Desk