Toxicity
Contract Research | Absorption/Transport
| Metabolism | Induction
| Physico-Chemical | Toxicity
| Sponsor-Initiated Protocols
 Hepatocyte
Toxicity
Hepatotoxicity is a major cause of drug candidate failure, both pre- and
post-market launch. In this test, the concentration of drug candidate
needed to cause 50% cell death in hepatocytes is determined. We would
measure ATP content of cells as an indicator of cell viability. The number
and spacing of drug concentrations is flexible.
Toxicity Testing in a Human Cell Line Engineered to Express P450
By using our MCL-5 cell line that expresses five human P450s (CYPs 1A1,
1A2, 3A4, 2A6 and 2E1) and epoxide hydrolase, we can create a toxicity
assay that is consistent over time and also avoids the variations in P450
expression that occur when dealing with human hepatocytes (Chem. Res.
Toxicol. 4:566 [1991])1. The human P450s incorporated into the MCL-5 cell
line are the major P450s implicated in creating toxic metabolites. The
MCL-5 assay can diff e rentiate between parent or metabolite toxicity
in one assay by comparing IC5 0 values with the control cell line cH2,
which does not contain the transfected genes. We measure oxygen respiration
as an indicator of cell viability although other assays are available.
The number and spacing of drug concentration is flexible.
Toxicity Services [ PDF
]
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Crespi, C.L., Gonzalez, F.J., Steimel,
D.T., Turner, T.R., Gelboin, H.V., Penman, B.W. and Langenbach,
R.A metabolically competent human cell line expressing five cDNAs
encoding procarcinogen-activating enzymes: application to mutagenicity
testing. Chem.Res.Toxicol.4:566 [1991].
Consult the ADME experts at 888.334.5229 or via email
to discuss your needs.
The complete FDA guidance document can be viewed on the web at:
http://www.fda.gov/cder/guidance/clin3.pdf
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