Site of Metabolism Predictions Facts and Experiences

Drug metabolism has been recognized as one of the key factors in the discovery of new chemical entities. A lead compound needs to not only interact with the target enzyme/receptor but also remain over a certain threshold concentration at the site of action for a defined period to produce the desired therapeutic effect. Drug metabolism together with absorption, distribution and excretion are among the factors that influence the final time-concentration relationship of drugs and therefore the potential efficacy of the compound [1], 

Copyright 2008 WILEY-VCH Veriag GmbH Co. KGaA, Weinheim ISBN 978-3-527-31821-6 

Several kinetic parameters can be measured on different experimental systems to account for the interaction of a compound with CYPs. For example when studying the metabolic stability of a compound, it could be measured in a recombinant CYP system, in human liver microsomes, in hepatocytes and so on. Each system increases in biological complexity. Although in the recombinant CYP system only the cytochrome under consideration is studied, in the case of the human liver microsomes, there is a pool of enzyme present that includes several CYPs, and finally in the hepatocyte cell system, metabolizing enzymes play an important role in the metabolic compound stability. In addition, transport systems are also present that could involve recirculation or other transport phenomena. The more complex the experimental system, the more difficult it is to extract information on the protein/ligand interaction, albeit it is closer to the in vivo real situation and therefore to the mechanism that is actually working in the body. 

Factors That Influence the Site of Metabolism Prediction by Cytochrome P450s 

There are at least two factors that could influence the turnover rate, the site of metabolism (hot spot) and the affinity of a compound toward these enzymes the protein/ligand (substrate or inhibitor) interaction and the chemical reactivity of the compound towards oxidation. Because of the interaction of the protein with the potential ligand, certain atoms of the compound could be exposed to the heme group, and depending on the chemical nature of these moieties the oxidative reaction will take place at different rates, for example celecoxib is metabolized by CYP2C9 at the 

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