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

[ Vol. 4 , Issue. 3 ]


Collen M. Masimirembwa, Richard Thompson and Tommy B. Andersson   Pages 245 - 263 ( 19 )


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.


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


Department of DMPK&Bioanalytical Chemistry, AstraZeneca, R and D Molndal, S431 83 Molndal, Sweden.

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