Drug metabolism database

Erhardt PW. A human drug metabolism database potential roles in the quantitative predictions of drug metabolism and metabolism-related drug-drug interactions. Curr Drug Metab 2003 4 411-22. 

IUPAC is constructing a human drug metabolism database model on the internet (286). This effort is based on the premise that very few published datasets are available for modeling (287,288), and even fewer sources outside the major pharmaceuticals are providing metabolism databases for various use by modeling groups. A version of this dataset is expected to be available in 2003, and it ultimately will serve as a standard for how new molecules are metabolized in humans. 

P. W. Erhardt, Ed., Drug Metabolism—Databases and High-Throughput Testing During... 

FIGURE 7.1 Ki in human liver microsomes for ketoconazole to inhibit the formation of 1-OH-midazolam from in vitro studies (data from 11 published articles from University of Washington Drug Metabolism database). 

FIGURE 7.2 Comparison of observed and predicted AUC changes of saquinavir with coadministration of ritonavir using different IC50 values from different substrates (data from University of Washington Drug Metabolism database). 

A new tool for computational ADME/Tox called MetaDrug includes a manually annotated Oracle database of human drug metabolism information including xenobiotic reactions, enzyme substrates, and enzyme inhibitors with kinetic data. The MetaDrug database has been used to predict some of the major metabolic pathways and identify the involvement of P450s [78]. This database has enabled the generation of over 80 key metabolic... 

Oxidative drug metabolism is extremely complex and possibly the most poorly understood ADME property. Rapid metabolism is unacceptable for drug candidates, except for drugs whose metabolite is the active moiety, because it causes duration of action to be too short. Considerable work has focused on the liver enzyme CYP3A4, which is responsible for the metabolic clearance of approximately 50% of marketed drugs. Recent approaches used to model and understand drug metabolism include database matching, quantum mechanics, QSAR, and structure-based analyses. 

Having access to metabolism data in the early discovery stage is invaluable. For example, hepatic metabolism data could be used to characterize the pharmacokinetic behavior of a perspective lead. Several studies have reported how metabolism databases and software systems have been used at various settings (272). In this section, we will provide an overview of recent databases, software systems, websites, tools, and services that could be potential starting points for metabolism modeling at various stages in drug discovery process (271,273). 

Obach, R.S., Lombardo, F. and Waters, N.J. (2008) Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 compounds. Drug Metabolism and Disposition The Biological Fate of Chemicals, 36, 1385—1405. 

These values were obtained from the University of Washington s Metabolism and Transport Drug Interaction Database http //www.druginteractioninfo.org rfOgilvie et al. (217). 

Metabolism and Transport Drug Interaction Database A Web-Based Research and Analysis Tool... 

An earlier version of the DIDB was described in Chapter 14 of the previous edition of this book (5). The new DIDB application launched in 2005 has a typical multitier architecture in a Microsoft . NET environment. The back end is a Microsoft SQL Server 2000 and the current application is deployed on a Web farm. Currently, the database has data extracted from more than 6280 published articles (1966 to 2007) related to drug metabolism and DIs and 260 product labels (1998 to 2007). The use of the Web facilitates worldwide access as well as upgrades and updates the DIDB is updated daily. 

Figure 2 List of precipitants evaluated with the substrates bupropion and efavirenz and which have shown more than 20% effect in in vivo inhibition. Display from the Metabolism and Transport Drug Interaction Database (http //www.druginteractioninfo...

Carlson SP, Ragueneau-Majlessi I, Levy RH. Development of a metabolic drug interaction database at the University of Washington. In Rodrigues AD, ed. Drugs and the Pharmaceutical Sciences, vol. 116. New York Marcel Dekker Inc, 2002 549-563. 

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