metabolites identified in urine, accounted for clearance of25% of the parent
dose. Therefore, a decision was made to conduct a ketoconazole drug–drug
interaction study to assess the effect of inhibiting CYP3A4 on the exposure of the
parent.
9.4 METABOLITES IN SAFETY TESTING (MIST)
A recent PhRMA perspective published by Baillie et al. outlines a consensus of
pharmaceutical industry representatives on monitoring metabolites in safety
studies (Baillie et al., 2002). This report discusses in detail the role of
metabolites in safety testing and decisions that are made based on data from
various in vitroand in vivo metabolism studies. Basically, the decision to
monitor metabolite(s) in humans and animals needs to be considered on a case-
by-case basis. A general guideline put forth by the PhRMA committee for a
metabolite that contributes to25% AUC of all the drug-related component is
to monitor this metabolite in human and animal studies. The FDA is planning
to provide their guidelines in the near future, however, based on their
comments in response to the PhRMA proposal and presentations at different
workshops over the past 2–3 years, it seems that they would like to see a more
stringent criteria (10% AUC) used to trigger considerations with regard to
(^0) 0 10203040506070
50
100
150
200
250
300
Feces 0-240 h
Time (min)
CPM
0 10203040506070
0
50
100
150
200
250
300
Bile 3–8 h
Muraglitazar glucuronide
O-Demethyl muraglitazar Muraglitazar
glucuronide
Hydroxy O-demethylmuraglitazar glucuronide
Hydroxy muraglitazar
glucuronide
Muraglitazar
Urea derivative of
muraglitazar
Urea derivative of
muraglitazarHydroxy muraglitazar
O-Demethyl muraglitazar
Hydroxy O-demethyl
muraglitazar
Dihydroxy muraglitazar
Feces 0-240 hFeces 0–240 h
Muraglitazar
Urea derivative of
muraglitazar
Urea derivative of
muraglitazarHydroxy muraglitazar
O-Demethyl muraglitazar
Hydroxy O-demethyl
muraglitazar
Dihydroxy muraglitazar
FIGURE 9.5 Radiochromatographic profiles of human bile and feces after oral
administration of [^14 C]muraglitazar. The profiles are a background subtracted
reconstructed radiochromatogram of 15-s fractions collected from an HPLC run.
METABOLITES IN SAFETY TESTING (MIST) 273