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Evaluation of fluorescence- and mass spectrometry-based CYP inhibition assays for use in drug discovery.

Bell, Leslie, Bickford, Shari, Nguyen, Phong, Wang, Jianling, He, Timothy, Zhang, Bailin, Friche, Yannick, Zimmerlin, Alfred Gilbert, Urban, Laszlo and Bojanic, Dejan (2008) Evaluation of fluorescence- and mass spectrometry-based CYP inhibition assays for use in drug discovery. Journal of Biomolecular Screening : the official journal of the Society for Biomolecular Screening, 13 (5). pp. 343-353. ISSN 1087-0571


The potential for metabolism-related drug-drug interactions by new chemical entities is assessed by monitoring the impact of these compounds on cytochrome P450 (CYP) activity using well-characterized CYP substrates. The conventional gold standard approach for in vitro evaluation of CYP inhibitory potential uses pooled human liver microsomes (HLM) in conjunction with prototypical drug substrates, often quantified by LC-MS/MS. However, fluorescent CYP inhibition assays, which use recombinantly expressed CYPs and fluorogenic probe substrates, have been employed in early drug discovery to provide low-cost, high-throughput assessment of new chemical entities. Despite its greatly enhanced throughput, this approach has been met with mixed success in predicting the data obtained with the conventional gold standard approach (HLM+LC-MS). The authors find that the predictivity of fluorogenic assays for the major CYP isoforms 3A4 and 2D6 may depend on the quality of the test compounds. Although the structurally more optimized marketed drugs yielded acceptable correlations between the fluorogenic and HLM+LC-MS/MS assays for CYPs 3A4, 2D6, and 2C9 (r2 = 0.5-0.7; p < 0.005), preoptimization, early discovery compounds yielded poorer correlations (r2 < or = 0.2) for 2 of these major isoforms, CYPs 3A4 and 2D6. Potential reasons for the observed differences are discussed.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: CYP inhibition; fluorogenic substrates; drug safety screening; human liver microsomes; drug-drug interactions
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Date Deposited: 14 Dec 2009 13:53
Last Modified: 31 Jan 2013 01:06