Exploratory drug metabolism

A landmark study reported that 40% of failures in clinical studies were due to PK problems.1-3 This led to the need to develop drug metabolism studies that could be performed on a compound before it was recommended for development. The early drug metabolism and pharmacokinetic (DMPK) studies were used to assess the ADME/PK properties of NCEs. The major pharmaceutical companies were very successful at setting up exploratory drug metabolism departments using various models. This led to an explosion of new higher throughput ADME/PK assays that provided medicinal chemists with the necessary tools to improve the ADME/PK properties of NCEs. 

DMDCT is an important parameter because it governs how quickly one can deliver ADME/PK data for certain parameters to a discovery team. The shorter the DMDCT, the more discovery cycles can be completed. For example, if the DMDCT is 1 month, a laboratory could handle 12 discovery studies per year at most. If the DMDCT is 2 weeks, 24 discovery cycles per year are possible. In the early days of exploratory drug metabolism, the DMDCT was typically 4 to 6 weeks, with at least 50% of the time dedicated to assay cycle time. Clearly, a new vision was required for the assay cycle. 

Exploratory Drug Metabolism Schering-Plough Research Institute Kenilworth, New Jersey, USA... 

Exploratory Drug Metabolism Department of Drug Metabolism and Pharmacokinetics... 

Walter A. Korfmacher, Director, Exploratory Drug Metabolism, Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033... 

Hsieh Y, Korfmacher W. The role of hyphenated chromatography—mass spectrometry techniques in exploratory drug metabolism and pharmacokinetics. Curr Pharm Des 2009 15(19) 2251-2261. 

Exploratory Drug Metabolism, Merck Research Laboratories, Kenilworth, New Jersey 07033... 

Waeter Koremacher Exploratory Drug Metabolism Merck Research Laboratories Kenilworth, New Jersey... 

Besides the examples listed above, there are numerous exploratory association studies that have identified many potential polymorphism biomarkers for treatment response in membrane transporter, drug-metabolizing enzyme, and drug target genes. The methodology and statistical analysis for the candidate gene approach are simple the results are easy to interpret. 

Reductive [ CJmethylation procedures have found broad application in the rapid labeling of investigational drug substances for in vitro studies where metabolism does not occur, in early exploratory in vivo investigations in drug research and development, and in peptide and protein mapping. However, because A -dealkylation reactions are common metabolic events, compounds labeled by Af-[ C]methylation are usually not suitable for registration studies. 

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