ADME studies metabolic stability

Thompson, T. N. Early ADME in support of drug discovery the role of metabolic stability studies. Curr Drug Metab 2000, 1, 215-241. 

In addition to the VolSurf treatment of the GRID fields, the information from the MIF can also be transformed to obtain a pharmacophoric type of representation, which is useful in the modeling of metabolic stability, cytochrome inhibition or even the direct study of the ADME related proteins (Fig. 10.3). The Almond software [17] transforms the MIF into a distance-based representation of the molecule interaction. These parameters describe the geometry of the interaction and QSAR models can be derived where the interaction with a protein is essential. Detailed information on these descriptors is presented elsewhere in this book. 

Thompson, TN. Early ADME in Support of Drug Discovery The Role of Metabolic Stability Studies, Curr. Drug Metab. 1(3), 215-241 (2000). 

Organotypic models, available for all organs involved in ADME, are used to study food matrix effects, intestinal metabolism/stability, and regional differences in permeability. The latter is of particular importance since it has been shown that permeability to various marker molecules varies along the intestinal tract in general, permeability decreases in the order jejunum > ileum > colon [54]. The half-lives of organotypic models limits the duration of possible studies to 1-3 hours. 

At the early stage of compound selection and optimization for deciding a clinical candidate, drug metabolism studies are often conducted in vitro with liver fractions and in vivo with rats using nonlabeled compounds to define metabolic stability, soft-spot identification, CYP inhibition/induction potential, bioactivation or toxic metabolite formation, major in vitro metabolic pathways, and the limited in vitro interspecies comparison. Mass balance (or ADME) studies with collection of plasma in animals and humans using a... 

Various in vitro assays are widely available for profiling distribution, metabolism, and pharmacokinetics (DMPK, also referred to as ADME absorption, distribution, metabolism, and excretion). Such properties of molecules are measured to ultimately predict their in vivo behavior. The metabolic stability of molecules is assessed routinely in drug discovery units by way of medium- to high-through-put assays using hepatic microsomes or hepatocytes obtained from different species (usually rat and/or human). Permeability assays (e.g., utilizing Caco-2 or MDCK cells) together with an assessment of efflux potential are also useful to troubleshoot unexpectedly low cell activity or can help select candidates for subsequent in vivo studies. 

As demonstrated in the case of SDZ HDC912 (5), identification of metabolically stable positions for placement of tritium is not always straightforward. Since the dog was identified to be a predictive species all isotopomers were tested in this species. Each of three isotopomers proved to undergo some metabolic loss of label, so that a large experimental effort had to be expended to find a label position of acceptable metabolic stability. In this case [5- H]SDZ HDC912 (5) was identified as the most suitable target for ADME studies in man. 

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