human subjects, and induction can be assessed by measuring the metabolism or
clearance of model substrates for the drug metabolizing enzymes of interest.
This method has the advantage of measuring directly in humans the end result
of induction, that is, enhanced drug metabolizing activity, and is therefore
undoubtedly the most relevant to actual clinical exposure. The disadvantage of
this model lies in its expense, and its potential hazard to experimental subjects
who derive no therapeutic benefit from exposure to the agent being tested.
These three approaches and their relative advantages and disadvantages will be
discussed.
17.2 Assessments
17.2.1 Assessment of Induction Potential Using Intact Animal Models
Intact animal models have long been used to predict drug–drug interactions in
humans, and have historically provided the primary model for investigating the
cellular events and mechanisms that mediate induction of drug metabolizing
enzymes by xenobiotics. Although we now recognize that the value of
preclinical studies in animals for predicting induction of drug metabolism in
humans may be limited, animal models have historically been very valuable in
both identifying and characterizing potential drug metabolism inducing agents.
They provide an intact, physiologically relevant system for presentation of the
putative inducer to the signaling system, as well as an intact signaling system
itself, complete with all intracellular and extracellular signaling modulators.
Furthermore, animal models provide expression of a complete drug
metabolism system, which potentially provides the expression of multiple
drug metabolizing enzymes that may be responsive to the inducing agent. This
complete system can therefore be used in carefully selected induction studies,
from overall in vivo clearance measurements to subcellular or molecular
mechanism studies, all in the same single integrated model.
However, intact animal models also have important limitations that may
diminish their efficiency and usefulness in screening for human induction
potential. They are a more expensive, lower throughput system thanin vitro
systems or cell culture. But certainly the primary drawback lies in the fact that
the molecular mediators of induction, including receptors and signaling
factors, that are present in animal species, may be very different, both
qualitatively and quantitatively, from those present in humans. The existence
of interspecies differences in the structure and function of receptors, and other
signaling molecules involved in induction, means that studies using common
laboratory animal species may poorly predict the ability of a drug candidate to
induce the same enzymes in humans. Considering the cost involved in large
scale animal studies, and their potential lack of predictive value, their efficiency
and usefulness in screening drug candidates for potential inducing activity must
now be questioned, especially in the light of newer well developed and readily
availablein vitroor cell culture screening systems. Animal-based screens may
548 TESTING DRUG CANDIDATES FOR CYP3A4 INDUCTION