Absorption, distribution, metabolism and excretion (ADME) studies are conducted
to determine the disposition of the drug and its metabolites in vivo.
The regulatory requirement for such studies in rodent and non-rodent species
used for the safety assessment of drugs reflects the importance of these data
in understanding and interpreting findings from pharmacological and toxicity
studies and in extrapolating to humans. Indeed ADME studies provide the bridge
between safety studies in animals to humans and support the relevance of safety
data generated in animal studies to humans.
The investigation of the metabolism and of the potential drug-drug interactions
of a test compound using human material in vitro is an essential predictive
tool that is used in both drug discovery and drug development. Comparing the
metabolism of a compound in cellular and / or subcellular preparations from
human with that from other species allows the selection of the most metabolically
relevant laboratory animal species to be used for toxicity testing during drug
development.
Furthermore, in vitro systems are especially useful to generate metabolites
for structural identification by LC-MS/MS and NMR. Elucidation of the interactions
of a test compound with human cytochrome(s) P450 (CYP) and other drug-metabolising
enzymes is important for predicting its potential for interacting with other
drugs. This information can then be used in decision-making on the future development
of the drug candidate and to plan relevant clinical studies.
In most geographical regions, there is no absolute requirement for ADME data
to be generated prior to initiating first in man studies provided that exposure
data have been generated in animal species used for early toxicity studies,
i.e. that pharmacokinetic and / or toxicokinetic data are available. However,
some preliminary ADME data are useful and indeed may be requested by the regulators
should there be any potential safety issues raised from early toxicity studies.
Many pharmaceutical companies conduct limited ADME studies before Phase I in
recognition of the usefulness of such data at this stage. Huntingdon Life Sciences
can provide appropriate protocols for early ADME studies on request.
It is also useful to generate early in vitro metabolism data at this
stage of development. Comparative metabolism (human vs. other species) and CYP
inhibition studies are particularly relevant here.
Once clinical pharmacokinetic data become available to supplement early non-clinical
safety data it is important to assess safety margins. As it is widely considered
that it is the proportion of the circulating drug that is unbound to plasma
proteins that is responsible for biological activity, safety margins should
be calculated based on 'unbound' rather than 'total' plasma levels of the drug.
Consequently, plasma protein binding studies should be conducted at an early
stage of the drug development process in order that appropriate calculation
of safety margins can be made.
Whilst some early metabolism data can be generated with non-radiolabelled test compounds, most definitive studies require the use of radiolabelled forms of the drug. Huntingdon Life Sciences has a long established radiosynthesis capability and our chemists would be pleased to discuss and support your needs for radiolabelled compounds, or indeed synthesis of stable isotope labelled forms (for use as internal standards in LC-MS/MS bioanalysis) or reference compounds for confirmation of putative metabolites.
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