since no parent peak is observed in the radioactivity profiles in both urine and
feces. All the metabolites that the humans generated are also observed in
animals suggesting that the primary pathways of metabolism is similar across
species. Taken together the metabolic profiles in plasma, urine, and feces help
us understand the complete disposition of drug.
For highly lipophilic drugs in the 300–700 Da range, metabolism and
excretion through the bile often plays a major role in their disposition. For
these types of molecules, conducting ADME studies in bile duct cannulated
(BDC) animals, where bile is collected during the duration of the study, is
extremely useful. BDC studies are particularly helpful if conjugative pathways
like glucuronidation or sulfation are involved in the metabolic clearance of the
drug. Glucuronide and sulfate conjugates, when excreted through the bile into
the gastrointestinal (GI) tract, can be hydrolyzed during their passage through
the intestine (Marier et al., 2002; Parker et al., 1980). Therefore, in the absence
of a bile profile the role of conjugation in the overall metabolic clearance of the
drug would be missed. BDC studies are usually run for a shorter duration,
24 h in rat and between 24 and 72 h in dog or monkey. These studies often do
not achieve full mass balance studies. Where nonclinical data shows that most
of the drug is excreted in the feces through bile as conjugative metabolites, it is
FIGURE 9.3 Comparative plasma profiles of radioactivity in rat, dog, and humans
showing parent and metabolites after a single oral dose of C-14-labeled compound. The
table in the figure shows the percent AUC of total radioactivity for parent (P) and two
major circulating metabolites in plasma samples. The AUCs for parent and metabolite
were generated from radioactivity profiles generated at several time points.
IN VIVOADME STUDIES 271