In Vitro High Throughput Screening of Compounds for Favorable Metabolic Properties in Drug Discovery.

Authors: Masimirembwa C.M.; Thompson R.; Andersson T.B.

Source: Combinatorial Chemistry & High Throughput Screening, Volume 4, Number 3, May 2001 , pp. 245-263(19)

Publisher: Bentham Science Publishers

Abstract:

Drug metabolism can have profound effects on the pharmacological and toxicological profile of therapeutic agents. In the pharmaceutical industry, many in vitro techniques are in place or under development to screen and optimize compounds for favorable metabolic properties in the drug discovery phase. These in vitro technologies are meant to address important issues such as (1) is the compound a potent inhibitor of drug metabolising enzymes (DMEs) (2) does the compound induce the expression of DMEs (3) how labile is the compound to metabolic degradation (4) which specific enzyme(s) is responsible for the compound biotransformation and (5) to which metabolites is the compound metabolized Answers to these questions provide a basis for judging whether a compound is likely to have acceptable pharmacokinetic properties in vivo. To address these issues on the increasing number of compounds inundating the drug discovery programs, high throughput assays are essential. A combination of biochemical advances in the understanding of the function and regulation of DMEs (in particular, cytochromes P450, CYPs) and automated analytical technologies are revolutionizing drug metabolism research. Automated LC-MS based metabolic stability, fluorescence, radiometric and LC-MS based CYP inhibition assays are now in routine use. Automatible models for studying CYP induction based on enzyme activity, quantitative RT-PCR and reporter gene systems are being developed. We will review the utility and limitations of these HTS approaches and highlight on-going developments and emerging technologies to answer metabolism questions at the different stages of the drug discovery process.

Keywords: High Throughput Screening; automated analytical technologies; DMPK research; acetyltransferases; robotic systems; fluoresence assays; CYP-specific chemical; transcriptionally-based induction; phenobarbital; pharmacokinetics

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1386207013331101

Publication date: 2001-05-01

• Combinatorial Chemistry & High Throughput Screening publishes full length original research articles and reviews describing various topics in combinatorial chemistry (e.g. small molecules, peptide, nucleic acid or phage display libraries) and/or high throughput screening (e.g. developmental, practical or theoretical). Ancillary subjects of key importance, such as robotics and informatics, will also be covered by the journal. In these respective subject areas, Combinatorial Chemistry & High Throughput Screening is intended to function as the most comprehensive and up-to-date medium available. The journal should be of value to individuals engaged in the process of drug discoveryand development, in the settings of industry, academia or government.

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