Metabolic screening in vitro: metabolic stability, CYP inhibition and induction

• Published in: Drug discovery today. Technologies 2004-12, Vol.1 (4), p.365-372
• Main Authors: Riley, Robert J., Grime, Ken
• Format: Article
• Language: English
• ISSN: 1740-6749; 1740-6749
• DOI: 10.1016/j.ddtec.2004.10.008

Automated, miniaturised assays are now commonplace within Discovery DMPK (drug metabolism and pharmacokinetics). These have evolved considerably since their inception around a decade ago, in-line with both technology and the desire to provide quality data comparable to more traditional analyses. Several formats exist for routine screening of metabolic stability and cyp (cytochrome P450; see Glossary) inhibition and induction, with the major focus being on in vitro systems using human-derived material. Data from other species remain valuable in assessing in vitro–in vivo projections and are pivotal to support safety assessment studies. Han van de Waterbeemd, Christopher Kohl – Pfizer Global Research & Development, Sandwich Laboratories, PDM (Pharmacokinetics, Dynamics and Metabolism), Sandwich, Kent, UK CT13 9NJ Metabolic issues can play a key role in the selection of appropriate clinical candidates and therefore screening of potential liabilities is performed in early discovery. Based on their wide industry experience, Robert Riley and Ken Grime review here technologies used to study metabolic stability as an early indicator for half-life. The metabolism of drugs can also lead to various safety issues. This review therefore in addition looks at technologies to estimate CYP (P450) inhibition and induction, both of which might be a concern for drug–drug interactions in the clinic and in the past have caused withdrawal of marketed drugs.