In Vitro Approaches for Studying the Inhibition of Drug-Metabolizing Enzymes and Identifying the Drug-Metabolizing Enzymes Responsible for the Metabolism of Drugs (Reaction Phenotyping) with Emphasis on Cytochrome P450

Victims are those drugs whose clearance is predominantly determined by a single route of elimination, such as metabolism by a single cytochrome P450 (CYP) enzyme. This chapter focuses on in vitro reaction phenotyping and CYP inhibition. A wide range of activity is also observed for many of the CYP enzymes that have a very low incidence of genetic polymorphisms. The primary purpose of evaluating drugs as inhibitors of CYP enzymes in vitro is to determine their perpetrator or precipitant potential before advancing a candidate drug to a late stage of development. An in vitro examination of time-dependent inhibition of the major drugmetabolizing CYP enzymes should be considered essential for drug candidates. Drugs such as tienilic acid not only pose a risk of prolonged inhibition of CYP enzymes, but they can also have wider implications. The use of pooled human liver microsomes for CYP inhibition studies is well documented.