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Drug Metabolism and Disposition Fast Forward
First published on November 15, 2006; DOI: 10.1124/dmd.106.012864

0090-9556/07/3502-275-282$20.00
DMD 35:275-282, 2007

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Induction of Cytochrome P450: Assessment in an Immortalized Human Hepatocyte Cell Line (Fa2N4) Using a Novel Higher Throughput Cocktail Assay

Kuresh A. Youdim, Christine A. Tyman, Barry C. Jones, and Ruth Hyland

Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom

Over recent years the application of cocktail studies to measure biological markers has become increasingly popular. The current study investigated a novel approach in assessing cytochrome P450 (P450) enzyme induction in an immortalized cell line using a cocktail of five P450 substrate probes compared with the traditional single-probe approach. The findings reported herein support use of a cocktail approach to assess the induction of the major P450s, namely, CYP3A4, CYP1A2, and CYP2C9. CYP2C19 and CYP2D6 could also be followed as part of the cocktail approach reported. Response to prototypical inducers did not differ to those observed in the presence of the specific probes alone. Consequently, this approach requires significantly fewer sample numbers if screening the induction potential of more than one P450. Moreover, these studies highlight the utility of the immortalized cell line Fa2N4 as a robust model system for induction studies. In conclusion, the current experimental setup is an improvement on current approaches used to assess P450 induction, significantly increasing sample throughput.

Address correspondence to: Kuresh Youdim, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich, Kent, UK. E-mail: kuresh.youdim{at}pfizer.com




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D. F. McGinnity, G. Zhang, J. R. Kenny, G. A. Hamilton, S. Otmani, K. R. Stams, S. Haney, P. Brassil, D. M. Stresser, and R. J. Riley
Evaluation of Multiple in Vitro Systems for Assessment of CYP3A4 Induction in Drug Discovery: Human Hepatocytes, Pregnane X Receptor Reporter Gene, and Fa2N-4 and HepaRG Cells
Drug Metab. Dispos., June 1, 2009; 37(6): 1259 - 1268.
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