Drug Metabolism in Drug Design and Development Basic Concepts and Practice

The effective dose equivalent in man in millirem (mrem) is calculated using
the following equation:

Radiation absorbed doseðmRadÞQðrem=RadÞWeighting Factorfor tissues

whereQ(rem/Rad) for [^14 C]-labeled compounds is 1(Weber et al., 1989).
Weighting factors for tissues are based on the recommendations of the
International Commission of Radiological Protection (ICRP) Publications 60
(ICRP Publication 60, 1990) and 30 (ICRP Publication 30, 1979). ICRP 60
weighting factors are applied to the values for bone marrow, large intestine,
liver, lung, skin, stomach, gonads, thyroid, and urinary bladder. ICRP 30
weighting factors are applied to the five remaining tissues with the highest
exposure.
According to federal guidelines (U.S. Food and Drug Administration,
1999), the limits for exposure to radioactivity for human volunteers in the
course of single dose studies with radioisotopes are 3000 mrem for exposure of
the whole body, active blood forming organs, lens of the eye, and gonads, and
5000 mrem for the tissue with the highest effective dose. Annual cumulative
limits are 5000 mrem for exposure of whole body, active blood-forming organs,
lens of the eye, and gonads, and 15,000 mrem for exposure of other organs.
Based on the pharmacokinetic and dosimetry data, administration of a
single oral 100-mCi dose of the radiolabel would not be expected to represent a
significant radiation exposure risk in man (Tables 18.A3 and 18.A4).

References

Baillie TA, Cayen MN, Fouda H, Gerson RJ, Green JD, Grossman SJ, Klunk LJ,
LeBlanc B, Perkins DG, and Shipley LA. Drug metabolites in safety testing. Toxicol
Appl Pharmacol 2002;182:188–196.

TABLE 18.A4 Calculated effective dose equivalent and organ doses compared
to the applicable FDA limits.

Dose limits (mrem)a Radiation

absorbed doseb

(mRad or mrem)

% Limit
(Single
Whole body or organ Annual Single study study)

Whole body (overall exposure) 5,000 3,000
Active blood forming organs 5,000 3,000
Lens of the eye 5,000 3,000
Gonads 5,000 3,000
Other organsc 15,000 5,000

NC Not calculated.
aFDA limit from US Food and Drug Administration 1999.

bCalculated for a 100-mCi dose of (^14) C- test article in humans.
cThe other organs with the highest estimated exposure.
602 ADME STUDIES IN ANIMALS AND HUMANS