8.5.3 Toxicology Mediated Through Metabolite Interaction
with Off-Target Receptors
The biotransformation of parent molecules often produces metabolites with
relatively minor structural alterations (addition of a hydroxyl group,
demethylation, etc.). As these changes may not be dramatic enough to depart
from the parent structure activity relationship, these metabolites may have
potent interactions with the same pharmacological target as the parent.
Although it is rare for metabolites to have greater potency than parent, a loss
of less that one order of magnitude is fairly common and the metabolites may
be potent enough to contribute to the overall pharmacological response.
Although it is fairly common for metabolites to potently interact with the
same pharmacological target as the parent, it is fairly uncommon for
metabolites to have potent interactions with other ‘‘off-target’’ receptors that
are not already affected by parent. Of course, this relationship will likely break
down as the dose and plasma concentration of drug and metabolites increase.
This relationship between dose and consideration of metabolite toxicity forms
the basis of arguments put forth by Smith and Obach (Smith and Obach, 2005)
that the metabolites of low dose drugs do not need to be characterized as
extensively as high dose drugs. The chances for new pharmacology would be
expected to increase for metabolites that result from major structural
alterations, but even in these cases there are relatively few examples of this
type of behavior. The chances for off-target pharmacology of metabolites
would also be expected to increase when the target is a member of a receptor
family with multiple related members (e.g., PPAR receptors, kinase families).
8.6 Assessment of Potential for Active Metabolites
In most cases, the metabolism of drugs leads to pharmacological inactivation
through biotransformation to therapeutically inactive molecules. However,
drug metabolism can also result in pharmacological activation, where
pharmacologically active metabolites are generated. Although formation
of pharmacologically active metabolites (bioactivation) can be mediated by
both oxidation and conjugation reactions, bioactivation resulting from
oxidative metabolism mediated by CYP enzymes is the more common
pathway.
Active metabolites may have superior pharmacological, pharmacokinetic,
and safety profiles compared to their respective parent molecules (Fura, 2006;
Fura et al., 2004). As a result, a number of active metabolites have been
developed and marketed as drugs with improved profiles relative to their
parent molecules. Examples of active metabolites of marketed drugs that have
been developed as drugs include acetaminophen, oxyphenbutazone, oxazepam,
cetirizine (Zyrtec), fexofenadine (Allegra), and desloratadine (Clarinex). Each
of these drugs provides a specific benefit over the parent molecule and is
superior in one or more of the categories described above.
ASSESSMENT OF POTENTIAL FOR ACTIVE METABOLITES 249