Predicting clearance in humans from in vitro data

• Published in: Current topics in medicinal chemistry Vol. 11; no. 4; p. 334
• Main Author: Obach, R Scott
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01-02-2011
• Subjects: Animals; Cytochrome P-450 Enzyme System - metabolism; Drug Design; Humans; Metabolic Clearance Rate; Microsomes, Liver - metabolism; Pharmaceutical Preparations - metabolism; Predictive Value of Tests
• ISSN: 1873-4294
• DOI: 10.2174/156802611794480873

The use of in vitro metabolism in scaling to predict human clearance of new chemical entities has become a commonplace activity in the research and development of new drugs. The measurement of in vitro lability in human liver microsomes, a rich source of drug metabolizing cytochrome P450 enzymes, has become a high throughput screen in many research organizations which is a testament to its usefulness in drug design. In this chapter, the methods used to scale in vitro clearance data to predict in vivo clearance are described. Importantly, the numerous assumptions that are required in order to use in vitro data in this manner are laid out. These include assumptions regarding the scaling process as well as technical aspects of the generation of the in vitro data. Finally, some other drug clearance processes that have been emerging as important are described with regard to ongoing research efforts to develop clearance prediction methods.