Early 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. 

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

Bugrim A, Nikolskaya T, Nikolsky Y. Early prediction of drug metabolism and toxicity systems biology approach and modeling. Drug Discov Today 2004 9 127-35. 

From an early drug discovery and hit triage perspective, a simplification that is typically made is to focus initially on CYP metabolism that occurs in the fiver. This simplification is appropriate for the majority of compounds - some compounds will be cleared by other mechanisms, but it is generally assumed that they must be relatively stable to CYP metabolism to achieve a desirable PK profile. 

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. 

High-Throughput Analysis in Drug Metabolism during Early Drug Discovery... 

Lloyd, T.L. et al. 2006. Laboratory automation for compound optimization and early development drug metabolism A Wyeth case study. Am. Drug Discov. 1 27. 

Lin, J.H. and Rodrigues, A.D. 2001. In vitro models for early studies of drug metabolism. In Pharmacokinetic Optimization in Drug Research Biological, Physicochemical and Computational Strategies. Testa, B. et al., Eds., Wiley, New York, p. 217. 

The advent of the atmospheric pressure ionization (API) source in the early 1990s allowed direct coupling of LC to MS. By the mid-1990s, this technology was a common in drug metabolism laboratories. The enhanced selectivity of tandem mass spectrometry (MS/MS) experiments reduced the need for exhaustive chromatographic separations prior to detection and this feature was exploited to significantly reduce analysis times. 

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