In vitro high throughput screening of compounds for favorable metabolic properties in drug discovery

Drug metabolism can have profound effects on the pharmacological and toxico logical profile of therapeutic agents. In the pharmaceutical industry, many in vitro techniques are in place or under development to screen and optimi ze 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 t he compound to metabolic degradation? (4) which specific enzyme(s) is respo nsible for the compound's biotransformation? and (5) to which metabolites i s the compound metabolized? Answers to these questions provide a basis for judging whether a compound is likely to have acceptable pharmacokinetic pro perties in vivo. To address these issues on the increasing number of compou nds inundating the drug discovery programs, high throughput assays are esse ntial. A combination of biochemical advances in the understanding of the fu nction and regulation of DMEs (in particular, cytochromes P450, CYPs) and a utomated analytical technologies are revolutionizing drug metabolism resear ch. Automated LC-MS based metabolic stability, fluorescence, radiometric an d LC-MS based CYP inhibition assays are now in routine use. Automatible mod els for studying CYP induction based on enzyme activity, quantitative RT-PC R and reporter gene systems are being developed. We will review the utility and limitations of these HTS approaches and highlight on-going development s and emerging technologies to answer metabolism questions at the different stages of the drug discovery process.