Drug Metabolism screening

PJ Eddershaw, M Dickins. Advances in in vitro drug metabolism screening. Pharm Sci Technol Today 2 13—19, 1999. 

Eddershaw, P.J. Dickens, M. Advances in In Vitro Drug Metabolism Screening, Pharm. Sci. Technol. Today 2(1), 13-19(1999). 

Bhoopathy, S.B. et al., A novel incubation direct injection LC/MS/MS technique for in vitro drug metabolism screening studies involving the CYP 2D6 and the CYP 3A4 isozymes, J. Pharm. Biomed. Anal., 37, 739, 2005. 

Quantitative In Vitro ADME Assays Using LC—MS as a Part of Early Drug Metabolism Screening... 

Roberts, S. A., High-throughput screening approaches for investigating drug metabolism and pharmacokinetics, Xenobiotica 31, 557-589 (2001). 

Solute uptake can also be evaluated in isolated cell suspensions, cell mono-layers, and enterocyte membrane vesicles. In these preparations, uptake is normalized by enzyme activity and/or protein concentration. While the isolation of cells in suspension preparations is an experimentally easy procedure, disruption of cell monolayers causes dedifferentiation and mucosal-to-serosal polarity is lost. While cell monolayers from culture have become a popular drug absorption screening tool, differences in drug metabolism and carrier-mediated absorption [70], export, and paracellular transport may be cell-type- and condition-depen-dent. 

Li, W., Josephs, J.L., Skiles, G. and Humphreys, W.G. (2008) Metabolite generation via microbial biotransformation with actinomycetes rapid screening methods and synthesis of important human metabolites of two development stage compounds, BMS-587101 and dasatinib. Drug Metabolism and Disposition The Biological Fate of Chemicals, 36, 721-730. 

The virtual compounds can be screened against structural models of the metabolizing enzymes, including the known SNP variants. These procedures are becoming widely adopted for the cytochrome P450 isozymes involved in oxidative drug metabolism. 

Genomic pre-screening of patients for SNP mutations in drug metabolism will improve the utility of clinical trials by focusing attention on the response of specific subpopulations to drug treatment. The consequence of this approach is that it should be possible to industrialize the creation of individual therapies, although at a significant increase in cost. 

White RE. High-throughput screening in drug metabolism and pharmacokinetic support of dmg discovery. Annu Rev Pharmacol Toxicol 2000 40 133-157. 

The drug discovery and development processes are time consuming and costly endeavors. It has been reported that on average it takes 10 to 15 years and costs more than 800 million to bring a molecule from discovery to market.12 Compounds fail for various reasons. One that accounts for a reported 40% of failures in clinical trials is poor pharmacokinetics.3 In an effort to improve the number of compounds that exhibit optimal absorption, distribution, metabolism, elimination (ADME), and pharmacokinetic (PK) properties and reach development, drug metabolism and pharmacokinetic scientists continually implement new technologies and compound screening approaches. 

Trubetskoy, O.V., Gibson, J.R., and Marks, B.D. 2005. Highly miniaturized formats for in vitro drug metabolism assays using vivid fluorescent substrates and recombinant human cytochrome P450 enzymes. J. Biomol. Screen. 10 56. 

Rodrigues, A.D., Preclinical drug metabolism in the age of high-throughput screening an industrial perspective, Pharm. Res., 14,1504,1997. 

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