higher volumes (such as ethanol, cremophor), that is substituted with water,
saline, buffer, etc.
In human ADME studies, generally, a fixed dose selected from a single or
multiple ascending dose study containing certain amount of radioactivity
(50–100mCi) is prepared in a formulation currently used in the clinic and dosed
to each human subject.
18.2.4 In-Life Studies in Animals and Humans and Sample
Collection/Pooling
Plasma, urine, bile, and fecal samples are obtained following a single oral or IV
administration of a radiolabeled drug to rats, mice, rabbits, dogs, monkeys, or
humans. In general, collection times for blood samples are chosen based on the
PK parameters of the drug, such ast1/2,Cmax(at least four time points, e.g., 1,
4, 12, 24 h, for metabolite profiling and multiple time points for PK analysis).
Urine and feces are collected at specific intervals from zero hours to the end of
the study, usually from 0 to 168 h.
18.2.4.1 Rat or Mouse Blood samples (at least four time points for metabolite
profiling) are obtained from male/female Sprague–Dawley rats and CD-1 mice
(three rats or three mice per collection time) by terminal bleeding via cardiac
puncture following carbon dioxide anesthesia. Urine (0–12, 12–24, and at 24 h
intervals thereafter throughout the study period) and feces (24 h intervals
throughout the study period) are collected from three rats or five mice on dry-ice.
In a separate study, bile, urine, and feces (0–24 h) are collected from three BDC
rats or five BDC mice for 0–24 h following oral or IV administration. For bile
collection, a bile salt solution (18 mg/mL cholic acid and 1.1 mg/mL sodium
bicarbonate in saline, pH 7.2) is infused via the duodenal cannula at 1 mL/h for
BDC rats or 0.3 mL/h for BDC mice. For the PK study, blood is collected from
three rats (200mL) via a jugular vein cannula or from five mice per time point by
terminal bleeding via cardiac puncture following carbon dioxide anesthesia at
various time points such as 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144,
and 168 h postdose.
18.2.4.2 Rabbit, Dog, or Monkey Blood (5–10 mL) at four or more time
points is collected from the indwelling venous catheter from three male and/
or female cynomolgus monkeys, male/female beagle dogs, or three female
New Zealand white rabbits. Urine (0–12, 12–24, 24 h interval thereafter
throughout the study period) and feces (24 h intervals throughout the study
period) are also collected on dry-ice. In a separate study, bile, urine, and feces
are collected (0–8, 8–24, 24–48 h for 0–48 h) from three bile duct cannulated
male animals. For bile collection, a bile salt solution (18 mg/mL cholic acid
and 1.1 mg/mL sodium bicarbonate in saline, pH 7.2) is administered via a
distal (flushing) catheter at 1 mL/kg/h for BDC animals. In addition, another
series of blood samples (2 mL) are collected at various time points such as
STUDY DESIGNS 579