Abstract
The rates and routes of the metabolism of a compound, as well as its potential to interfere with the metabolism of other, co-administered compounds, can often be the major factors that determine the clinical usefulness of a drug. There are, therefore, obvious economic advantages in being able to make predictions of these factors in drug discovery, thus enabling informed choices to be made between candidate molecules in a discovery series. Many of the major drug-drug interactions recognised to date occur at the level of liver cytochromes P450. All of the major human cytochromes P450 involved in drug metabolism have been cloned and expressed in transformed cell lines. These are commercially available, either as the original cell lines, or as microsomes or purified enzyme prepared from them. In these formats, the P450s can be used to determine the enzymology of a compound's metabolism and its potential for inhibition-based interactions. Current adaptations of the methods used in these types of study are enabling expressed P450s to be used in high throughput metabolism screens. It is possible that, in the future, they will also be incorporated into novel techniques, such as hyphenated screening systems. Thus, the expressed P450s will continue to be an important tool for drug discovery in the pharmaceutical industry.
