Drug Metabolism Letters

Zhiyang Zhao
Amgen
Cambridge, MA
USA

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High-Throughput Evaluation of CYP1A1 and 2B1 Induction in Rat Liver Slices Using a Semi-Automated System

Author(s): Jairam R. Palamanda, Xinjie Lin, Pramila Kumari, Amin A. Nomeir.

Abstract:

Drug candidates with the propensity to induce rat CYP1A1 or 2B1 isoforms are believed to possess a greater tendency to induce hepatic tumors in oncogenicity studies. We have previously published on a manual rat liver slice assay that showed a satisfactory relationship between in vitro CYP2B1 m-RNA induction using real time PCR and the ex vivo pentoxyresorufin O-dealkylase (PROD) activity in liver microsomes prepared from rats treated daily via the oral route for 14 consecutive days with inducers or non-inducers. We now describe this automated in vitro high throughput liver slice technique to screen out drug candidates that are potent rodent CYP1A1 and/or CYP2B1 inducers. A good concordance between in vitro and in vivo data was observed for both CYP1A1 (100 %) and CYP2B1 (90%) isoforms. Automation of key steps has enabled us to increase the annual screening throughput from 200 (manual) to 1500 compounds. The increase in throughput allowed the quick development of structure-induction relationships (SIRs) for multiple drug discovery programs in a facile manner.

Keywords: Automation, HTP or High Throughput, Liver Slices, Real Time PCR, Cytochrome P450, Induction, CYP1A1, CYP2B1

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Article Details

VOLUME: 3
ISSUE: 2
Year: 2009
Page: [108 - 114]
Pages: 7
DOI: 10.2174/187231209788654108
Price: $58