A computer program for automated data evaluation to support in vitro higher‐throughput screening for drug metabolism and pharmacokinetics attributes

Abstract

With the advances in analytical techniques, higher-throughput screening for drug metabolism and pharmacokinetics (DMPK) attributes has become an integral part of drug discovery. However, as the number of compounds increases, the volume of data that needs to be processed and evaluated increases exponentially. As a result, a major challenge for the analytical chemist is how to quickly process the vast amount of data so as to keep up with the throughput of the screening assay. We have developed a customized computer program for automated evaluation of the liquid chromatography/tandem mass spectrometric (LC/MS/MS) data generated from the in vitro DMPK screening assays. This program performs automatic data processing and quality control. It identifies analytical anomalies, such as low internal standard intensity and poor reproducibility of replicates. All analytical anomalies for individual compounds are summarized into an 'E-Log' in a color-coded format for reviewing. With the use of this program and other supporting software, data processing and evaluation for up to 100 compounds are accomplished in several minutes.

Validation of a high‐throughput absorption, distribution, metabolism, and excretion (ADME) system and results for 60 literature compounds

“…However, a major component of such systems is software that is designed to take advantage of the best of current tools. Such software is not currently commercially available and is the major focus of current publications in the field 10, 14. A major hurdle in attempting to achieve this goal was therefore to collaborate with a firm willing to commercialize the software in exchange for our help in writing and troubleshooting it.…”

Recent development in high-throughput bioanalytical support forin vitroADMET profiling

“…QuickQuan in particular also features a fully integrated module to support staggered parallel LC-MS/MS analysis using the Thermo/Cohesive AriaÔ multiplexing system. Finally, new user interfaces specially designed for ADMET bioanalytical data review have also been developed based on previous work by several research groups [74,119,157]. For instance, the approach of 'multiple injection chromatogram' [36,121], which displays multiple injections for the same compound in one assay as one single chromatogram, greatly simplifies the peak integration review for ADMET assays and has been adopted by vendors.…”

“…From the perspectives of the bioanalytical group supporting ADMET profiling, one remaining informatics challenge lies in the integration of the vendor software (such as QuickQuan or DiscoveryQuant) into their organizations' existing lead discovery and ADMET profiling informatics infrastructure such as compound submission system, assay request system, laboratory information management system and electronic lab notebook system. Historically, this was done through the use of simple tools developed with Excel or Visual Basic for Applications by the researchers [157,159]. More recently, there is a growing trend for the ADMET bioanalytical group to develop and implement dedicated workflow software tools that manage the information flow throughout the assay process, and also serve as an intermediate between the vendor software solutions and the enterprise informatics infrastructure.…”

Increasing high‐throughput Discovery bioanalysis using automated selected reaction monitoring compound optimization, ultra‐high‐pressure liquid chromatography, and single‐step sample preparation workflows

“…These transitions occur as the precursor or parent ions fragment in the collision cell to produce product ions specific to that molecule. Each vendor who provides mass spectrometry instruments has produced software that can automate the SRM process such that a scientist is not required to be at the instrument 18–23. For Sciex instruments (Applied Biosystems) the software is called Automaton and DiscoveyQuant, for Micromass instruments (Waters) it is labeled QuanOptimize, and, for Finnigan instruments (Thermo Scientific), it is designated as QuickQuan, to name but a few, but this list is not inclusive.…”