useful to include a panel in the human ADME study where bile can be
collected. There are several methods for this that has been recently reviewed
(Ghibellini et al., 2006). This is exemplified in Fig. 9.5 for an ADME study
conducted with [^14 C] muraglitazar, where bile was collected for a short
duration (3–8 h) after dosing. When the bile profile is compared against fecal
profile it can be clearly seen that the dose in the bile is excreted as conjugates
that is hydrolyzed during their passage through the GI tract (Wang et al.,
2006).
The data from the human ADME study provides information about the
primary pathways of metabolism for the compound. This is based on the
identification of metabolites in plasma, urine, and feces/bile. This in turn can lead
to detailed reaction phenotyping studies that is performed to identify the enzymes
that generate the primary metabolites. Furthermore, metabolism data from
human ADME studies in conjunction with reaction phenotyping can drive
decisions regarding the conduct of key drug–drug interaction studies. For the
example illustrated in Fig. 9.3, reaction phenotyping studies showed that the
monohydroxylated and O-demethylated metabolites were generated mainly by
CYP3A4. Moreover, metabolism through these pathways, based on the
FIGURE 9.4 Radiochromatographic profiles of pooled urine and fecal samples in rat,
dog, and human administered a single oral dose of [^14 C] gemopatrilat. The profiles are a
background subtracted reconstructed radiochromatogram of 15-s fractions collected
from an HPLC run.
272 ROLE OF DRUG METABOLISM IN DRUG DEVELOPMENT