18.4.2 Metabolite Profiles in Plasma, Urine, Bile, and Feces
In order to determine the metabolic fate of a radiolabeled drug, radioactivity in
plasma, urine bile and feces is profiled for metabolite distribution. Metabolite
profiling in muraglitazar study is described below.
18.4.2.1 Plasma The extraction recovery of radioactivity from all plasma
samples was greater than 98%. The HPLC radiochromatographic profiles of
1-h plasma from rat, dog, monkey, and human are shown in Fig. 18.2. The
relative distribution of radioactive metabolites in pooled plasma (rat, monkey
and human) is summarized in Table 18.6. The metabolic profiles of plasma
were qualitatively similar at different time points within species and across
species. Muraglitazar was the major component at 1, 4, and 12 h, accounting
for more than 90% of plasma radioactivity at 1 h in all four species. All
metabolites (M1, M2, M5, M8, M8a, M10–13, and M18) observed in human
plasma were also present in rats, dogs, or monkeys.
TABLE 18.6 Distribution of radioactive metabolites in pooled plasma after an oral
dose of [^14 C]muraglitazar to rats, monkeys, and humans.
Meta Distribution of Metabolites (% of sample)a
Rat Monkey Human1h 4h 12hb 1h 4hb 12 h 1 h 4 hb 12 hM1 NDc ND 0.05 0.3 0.3 ND ND Trace 0.2
M2 ND ND 0.05 ND 0.1 ND ND Trace NA
M5 ND ND Traced 1.5 2.9 2.7 ND 0.3 1.0
M6 ND ND Trace ND Trace ND ND ND ND
M8 ND ND Trace 1.0 1.5 1.0 ND Trace ND
M8a ND ND Trace 0.9 1.3 1.0 ND Trace ND
M10 ND ND 0.2 0.9 1.6 0.4 ND 1.0 1.0
M11 ND ND Trace 8.0 16.2 21.4 ND 0.3 ND
M12 ND ND Trace ND Trace 0.5 ND 0.2 ND
M13 ND ND 0.05 0.1 0.2 0.1 2.5 4.2 2.5
M15 2.3 2.1 3.5 0.1 0.3 ND 0.2 0.5 0.4
M18 ND ND Trace ND 3.1 4.0 ND 0.3 ND
M20 ND ND 0.4 0.1 0.2 0.4 ND ND ND
P 95.9 95.3 92.2 85.1 67.6 65.9 97.1 92.2 94.0
Othere 6.8 10.5 1.6 5.5 1.1 0.6 1.3 0.6 0.2
Total 98.2 97.4 96.6 98.1 92.9 97.1 99.8 99.0 98.1
aRadioactive peaks are reported as a percentage of the total radioactivity eluted from the column.
Column recoveries were>98%.
bLC/MS analysis was performed on this plasma sample.
cND = not detected. Criteria are no discernible radioactive peak,<0.05% radioactivity and not
detected by LC/MS.
dTrace =<0.05% radioactivity and detected by LC/MS.
eOther = not identified peaks.
DATA PRESENTATION USING METABOLISM OF [^14 C]MURAGLITAZAR 591