dose is readily excreted from the body. The amount of radioactivity is usually
expressed as the percent of the dose in each matrix (urine, feces, bile, etc). A
hundred percent of recovery of the administered radioactive dose is usually not
possible. Both in animal and human mass balance studies, a recovery of>85%
of the administered radioactive dose would be best although there is no specific
number requirement from regulatory agencies. A long elimination half-life of
the drug and radioactivity binding to tissues are some of the causes for low
recoveries. In addition, the radioactive drug related compounds may be lost
through expiration if the drug is volatile.
The recovery values of radioactive doses in urine, bile, and feces of rats,
monkeys, and humans administered [^14 C]muraglitazar are shown in Table 18.3
as an example. Urinary excretion of radioactivity was low (1.0, 0.5, 3.7, and
2.6% of dose for intact rats, dogs, monkeys, and humans, respectively) and the
primary route of excretion was feces (87.7, 89.0, 80.4, and 61.6% of dose for
intact rats, dogs, monkeys, and humans, respectively). The bile contained the
majority of radioactivity from rats, mice, monkeys, and humans, representing
the major elimination pathway of [^14 C]muraglitazar in these four species
(Table 18.3). Table 18.4 shows the total concentrations of muraglitazar and its
metabolites excreted in urine and bile in rats, dogs, monkeys, and humans.
TABLE 18.4 Approximate concentrations of [^14 C]muraglitazar and metabolites in
urine and bile from rats, mice, dogs, monkeys, and humans following oral
administration.
Rat Dog Monkey HumanUrine
Dose (mg/kg or mg/subject) 11 2 1.9 10
Body mass (kg)a 0.25 10 5 70
Urine collection interval (h)b 0–12 0–24 0–12 0–8
Concentration in urine (mg eq/mL)c 1.60 0.20 0.57 0.17
% Dose in urine of interval collection 0.51 0.49 1.7 1.3
Rat Mouse Monkey Human
Bile
Dose (mg/kg or mg/subject) 10 1, 40 5 20
Body mass (kg)a 0.25 0.02 5 70
Dose/subject (mg) 2.5 0.02, 0.8 25 20
Bile Flow (mL/h)a 22.5 2 125 350
Bile collection interval (h) 0–24 0–24 0–48 3–8
Concentration in bile (mg eq/mL)d 0.289 0.375, 13.2 0.007 0.068
% Dose in bile of interval collection 65.1 75, 66 36 40
aLiterature values from Davies and Morris (1993).
bClosest matched intervals; highest concentrations were excreted in these intervals.
cTotal concentration of muraglitazar plus all metabolites (muraglitazar equivalents).
dTotal concentration of muraglitazar plus all metabolites (muraglitazar equivalents). Calculated
based on theoretical bile excretion volume in 0–24 or 0–48 h for animals and 0–8 h for humans.
The bile concentration in rats was an assumption only since there is no gallbladder in the rat.
DATA PRESENTATION USING METABOLISM OF [^14 C]MURAGLITAZAR 587