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Journal of Biomolecular Screening
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A High-Throughput Method for Enzyme Kinetic Studies

Lakshmi D. Saraswat

Departments of Biology and Bioanalytical Chemistry, ArQule, Inc., Woburn, MA, lsaraswat{at}arqule.com

Kimberley A. Caserta

Departments of Biology and Bioanalytical Chemistry, ArQule, Inc., Woburn, MA

Kathy Laws

Millennium Pharmaceuticals, Inc., Cambridge, MA

Darren Wei

Cantata Pharmaceuticals, Woburn, MA

Simon S. Jones

Departments of Biology and Bioanalytical Chemistry, ArQule, Inc., Woburn, MA

Adedayo Adedoyin

Aventis Pharmaceuticals, Bridgewater, NJ

A simple and flexible setup for conducting drug metabolism studies is described in this report. A heating block was designed for the Multimek liquid handler platform for incubation of multiple samples at 37 °C in a 96-well format. This setup enables the rapid performance of drug metabolism experiments on a large number of samples. In this report, the authors present the validation of the system by 1) showing reproducible and consistent determination of the in vitro half-life of midazolam in every well across the entire plate and 2) determination of metabolic parameter values of midazolam, testosterone, diclofenac, warfarin, and dextromethorphan and inhibition parameter values of quinidine and ketoconazole, all comparable to literature values. In addition, the authors demonstrate the application of the setup to determining the metabolic stability of a set of proprietary compounds, the inhibition of activity of cytochrome P450 (CYP) enzymes, and the conduct of a single combination experiment that can simultaneously determine the metabolic stability and CYP inhibition activity. Overall, the system represents a simple, high-throughput and useful tool for drug metabolism screening in drug discovery. (Journal of Biomolecular Screening 2003:544-554)

Key Words: drug metabolism • enzyme kinetics • high-throughput screening • cytochrome P450 inhibition

Journal of Biomolecular Screening, Vol. 8, No. 5, 544-554 (2003)
DOI: 10.1177/1087057103257290
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