Drug Metabolism in Drug Design and Development Basic Concepts and Practice

from time 0 to the last time point (AUC0–t), and area under the concentration–
time curve from 0 to infinity (AUC0– 1 ), are calculated by using kinetica and
presented in Table 18.A2.
For dosimetry calculations, the concentrations of total radioactivity in rat
tissues from a tissue distribution study are used as the basis for calculating the
estimated radiation exposure in humans following a 100-mCi oral dose of [^14 C]-
test article. Pharmacokinetic parameters generated by WinNonLin are trans-
ferred into Excel Version 8.0e (Microsoft Corporation) for calculation of
human dosimetry parameters.
The dose exposure to each tissue or matrix (mCi/h) is calculated using the
following equation.

AUC 0 1ðmgeq h=gÞtest article specific activityðmCi=mgÞ

ð%Tissue weight=Actual dose in ratsmCi=gÞ

TABLE 18.A1 Concentrations of radioactivity in plasma, blood, and tissues at 1 h
following a single oral dose ofxmg/kg dose of radiolabeled test article in male Long–
Evans rats.

Nanogram equivalents of drug X/g

Animal number

Tissues R1 R2 R3 Mean SD

Adrenal gland
Bile
Blood
Bone
Bone marrow
Cecum
Cecum contents
Cerebellum
Cerebrum
Cerebrospinal fluid
Diaphragm
Epididymis
Esophageal contents
Esophageal mucosa
Esophagus
Exorbital lacrimal gland
Eye
Eye (lens)
Fat (abdominal)
Fat (brown)

BLQ Below the limit of quantitation.
SD Standard deviation.

CONCLUSIONS AND PATH FORWARD 599