Active Metabolites or Pharmacologically Active Metabolites The term refers to
a metabolite that has target pharmacological activity greater than, equal to, or
less than the parent drug.
Important Active Metabolites The MIST document defines an important
active metabolite ‘‘as one which is deemed to make a significant contribution to
the total known pharmacological activity of a given dose of the parent
compound.’’ The FDA draft guidance document does not use this term.
Structural Alerts The term refers to a metabolite that belongs to a chemical
class with known toxicity, a metabolite that contains positive structural alerts
for certain toxicity, or a GSH adduct/mercapturic acid conjugate indicative of
a trapped reactive intermediate.
7.3.5.2 Selection of Metabolite(s) for Pharmacological Activity Testing
Understanding whether a circulating metabolite in humans makes a
significant contribution to the drug-related target pharmacological effect
has important implications for selection of the metabolite for monitoring
using a bioanalytical method and for safety testing. Therefore, it is a common
practice to test the pharmacological activity of the major human plasma
metabolites. It should be also considered for pharmacological activity testing
if a unique metabolite is identified in humans or a significant nonlinear PK/
PD relationship is observed in humans or preclinical species. Pharmacological
activity testing of a metabolite, especially a plasma metabolite, often requires
time- and resource-consuming processes, namely definitive metabolite
identification by LC/MS and NMR followed by chemical synthesis. In
some cases large-scale metabolite isolation from urine or bile may provide
sufficient amounts of metabolite(s) for activity testing. Because of resource
restrictions, it is often not feasible to test the pharmacological activity for all
major metabolites in humans or animals. Both the MIST document and the
FDA draft guidance have suggested that the pharmacological activity of
metabolites is an important factor in the consideration of metabolite
monitoring and safety testing. However, these documents do not elaborate
what types of metabolites should be tested for receptor-mediated pharma-
cological activity. We believe that the issue should be handled on a case-by-
case basis.
7.3.5.3 Selection of Metabolite(s) for Monitoring in Clinical Studies and
Nonclinical Toxicological Studies The objective of the metabolite measure-
ment using a bioanalytical assay, such as an LC/MS method, is to determine its
pharmacokinetic parameters (such as AUC andCmaxvalues) of a specific
metabolite. The MIST document recommends quantifying certain human
plasma metabolites, including ‘‘major metabolites,’’ ‘‘important active
metabolites,’’ and ‘‘metabolites associated with structural alerts’’ using a
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