(1) a decreased clearance may translate into a lower overall dose;
(2) lower rates of formation and overall amounts of reactive intermediates
that may mediate acute or idiosyncratic toxicities;
(3) increased pharmacokinetic half-life that will hopefully translate into a
longer duration of action, less frequent dosing, and better patient
compliance;
(4) better understanding of the extrapolation of animal data to humans,
making human dose projections more reliable, and reducing risk upon
entry into clinical development;
(5) lower risk of drug–drug interactions, even if the compound is still
dependent on metabolism for the bulk of its clearance, low clearance
drugs are less susceptible in drug–drug interaction caused by the
coadministration of inhibitor;
(6) lower risk of drug–food interactions due to the reduced dose;
(7) decreased formation of metabolites that may have pharmacological
activity against the target or may have significant off-target
activity.These considerations make it important to understand the metabolism
characteristics of candidate drug molecules and to optimize these character-
istics preclinically when possible. Drug metabolism plays a central role in
modern drug discovery and candidate optimization, and recent reviews have
detailed how metabolism has impacted the discovery process and challenges
that the field faces in the future (Cox et al., 2002; Smith et al., 2002; Thompson,
2001; White, 2000).
This chapter will give an overview of metabolism-related topics that are
often incorporated into drug discovery efforts in an effort to advance the
optimal drug candidate into clinical investigations. Many of the topics covered
briefly in this chapter will also be covered in more depth in other chapters of
this book.
8.2 Metabolic Clearance
8.2.1 General
The metabolic clearance of NCEs is most often studied with a combination of
in vitroandin vivoapproaches. There are severalin vivoapproaches that can be
used to study metabolism in preclinical species and these along within vitro
results can often shed mechanistic insight into the problems associated with rapid
metabolic clearance and incomplete oral bioavailability due to first-pass
metabolism. Modern LC–MS/MS measurement of plasma drug concentrations
provide a rapid tool to assess oral bioavailability of new candidate compounds
and allows for early definition of bioavailability problems. When bioavailability
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