Reaction phenotyping studies are conducted at multiple stages in the drug
development process. Earlier studies performed during the drug discovery
stages measure loss of the parent to understand the potential liability
associated with clearance by a single polymorphic enzyme. Detailed reaction
phenotying studies are often conducted after results from the human ADME
become available. As indicated in the ADME section of this chapter, the
human study with radiolabeled drug is an information rich study that helps
understand: (1) if metabolism is responsible for clearance of a drug, (2) if a
major metabolic pathway contributes to>25% of clearance, and (3) if there
are major circulating metabolites. Once the primary pathways that contribute
to 25% of the clearance have been identified, then detailed reaction
phenotyping studies should be performed to identify the enzyme(s) responsible
FIGURE 9.6 Comparativein vitroprofile in liver microsomes and hepatocytes of rat,
monkey, and human incubated with [^14 C]dasatinib. The profiles are radiochrotogram of
HPLC eluant flowing through an online IN/USb-Ram radioactivity detector.
276 ROLE OF DRUG METABOLISM IN DRUG DEVELOPMENT