major clearance pathways. The ADME data will also define relative concentra-
tions of each metabolite in plasma, urine, bile, and feces. Since one of the main
objectives for metabolism studies is to support drug safety evaluation studies, the
Metabolite In Safety Testing (MIST) committee suggested that any circulating
metabolites and any significant metabolites in excreta of humans should be
characterized to understand the formation pathways of metabolites (Baillie et
al., 2002). Identification of the major metabolites in human excreta not only aids
in defining the major clearance pathways but also designing the drug–drug
interaction studies. Major metabolites in animals, which may not be important
as human metabolites, should also be identified since they may explain the
species-specific toxicities observed in animals. Thus, there is a need to identify
quantitatively and qualitatively important radioactive metabolites in studies
with radiolabeled materials.
A study protocol including any amendment for ADME studies should be
finalized before the experimental start date. The ADME studies are not
generally conducted under the Good Laboratory Practice (GLP) Regulations;
however, the Standard Operating Procedures (SOP) of the Test Facility should
be followed. All animal housing and care conformed the standards
recommended by the Guide for the Care and Use of Laboratory Animals.
Human ADME studies are performed in accordance with the following codes
and guidelines: Title 21, Part 56 CFR (Institutional Review Board Approval);
Title 21, Part 50 CFR (Protection of Human Subjects); European guidelines
(Lellig, 1996; Nuis, 1997); the principles of the Declaration of Helsinki and its
amendments; and Good Clinical Practice. The purposes of these guidelines are
for the safe and effective use of the radioactive drugs. Based on the tissue
distribution study in rats, the extrapolated radiation dose equivalent for tissues
in humans following single 50–100mCi doses would be lower than the annual
allowable exposure limits (3000 mrem) (Appendix A describes a typical rat
tissue distribution study and dosimetry calculation). In addition, all subjects
were advised of the nature and risks associated with the study and required to
give informed and written consent prior to participation in the study. All
subjects are acceptable as determined by medical history, physical examination,
and clinical laboratory tests conducted prior to study based on inclusion and
exclusion criteria. Dosing a radiolabeled material to human subjects is not
generally done as the first human study although there is no regulation dictating
not to do so. Considering the amount and type of information that a human
ADME study can provide, it should be conducted earlier in the program, for
example, right after the multiple ascending dosing study or parallel to it.
At the early stage of compound selection and optimization for deciding a
clinical candidate, drug metabolism studies are often conductedin vitrowith
liver fractions andin vivowith rats using nonlabeled compounds to define
metabolic stability, soft-spot identification, CYP inhibition/induction poten-
tial, bioactivation or toxic metabolite formation, major in vitrometabolic
pathways, and the limitedin vitrointerspecies comparison. Mass balance (or
ADME) studies with collection of plasma in animals and humans using a
574 ADME STUDIES IN ANIMALS AND HUMANS