In addition to determine the major metabolic pathways of a drug, the
radioactivity and the unchanged drug concentration in blood, plasma, urine,
and feces obtained from mass balance studies can provide information about
the pharmacokinetic behavior of a drug. As summarized by Beumer et al.
(2006), the pharmacokinetic parameters for unchanged drug can be determined
from the plasma data (obtained from e.g., LC/MS analysis). These parameters
includeCmax(maximum drug concentration),Tmax(time to reach maximum
concentration), AUC (area under the plasma concentration–time curve),Vd
(volume of distribution) andt1/2(elimination half-life). These results should be
comparable to the results from other pharmocokinetic studies (for both human
and animal). These parameters can also be calculated using the radioactivity
data. Elimination half-life from plasma will be used to determine if the drug
metabolites are accumulated upon multiple dosing. The ratio of the AUC of
the unchanged drug to total radioactivity AUC will provide information about
how much the metabolites are important (Slatter et al., 2000; Walle et al.,
1995). Pharmacokinetic parameters of urine together with those of plasma
provide data to determine the renal clearance of the drug.
The muraglitazar pharmacokinetic parameters for the unchanged drug and
radioactivity are presented in Table 18.5. The animal and human plasma
concentration time profiles for radioactivity and muraglitazar are presented in
Fig. 18.1. Following oral administration, the radioactivity and muraglitazar
concentrations reached a maximum at 0.5–1 h in rats, dogs, monkeys, and
humans.
TABLE 18.5 Mean pharmacokinetic parameters of muraglitazar in rats, dogs,
monkeys, and humans following oral administration of [^14 C]muraglitazar.
Species (n) Dose Analyte
Cmaxa
(mg/mL)Tmax
(h)AUC0–ta
(mg h/mL) t1/2b(h)Rat (3) 10 mg/kg Muraglitazar 12.83.0 0.5c 101 20 10.30.4
Radioactivity 13.52.6 0.5c 105 19 3.81.8
Dog (3) 2 mg/kg Muraglitazar 0.80.4 0.5 1.30.4 5.74.6
Radioactivity 1.00.4 1 1.10.4 d
Monkey (3) 1.9 mg/kg Muraglitazar 6.92.5 1e 41 9 18.02.1
Radioactivity 7.12.1 1e 71 8.3 23.511.7
Human (6) 10 mg Muraglitazar 1.80.4 1 12 2.8 35.19.7
Radioactivity 1.40.4 1 9.03.1 19.88.5
aUnits forCmax: muraglitazar (mg/mL) and radioactivity (mg-equivalents/mL); units for AUC:
muraglitazar (mg h/mL) and radioactivity (mg-eq h/mL). Last detectable time points for respective
parent compound and the radioactivity were 96 and 24 h for rat, 12 and 4 h in dog, 144 and 24 h
for monkey, and 192 and 72 h for human.
bThet1/2values for radioactivity were lower than the parent for rats, dogs, and monkeys because
the detection limit for radioactivity was approximately 15–30 times higher than LC/MS-based
parent determination.
cSecond peaks were observed at 8 h in rats.
dNot determined due to limited time points.
eSecond peaks were observed for at 6 h in monkeys.
588 ADME STUDIES IN ANIMALS AND HUMANS