Evolution of an open‐access quantitative bioanalytical mass spectrometry service in a drug discovery environment

Abstract

Increased demand for assays for compounds at the early stages of drug discovery within the pharmaceutical industry has led to the need for open-access mass spectrometry systems for performing quantitative analysis in a variety of biological matrices. The open-access mass spectrometers described here are LC/MS/MS systems operated in 'multiple reaction monitoring' (MRM) mode to obtain the sensitivity and specificity required to quantitate low levels of pharmaceutical compounds in an excess of biological matrix. Instigation of these open-access systems has resulted in mass spectrometers becoming the detectors of choice for non-expert users, drastically reducing analytical method development time and allowing drug discovery scientists to concentrate on their core expertise of pharmacokinetics and drug metabolism. Setting up an open-access facility that effectively allows a user with minimal mass spectral knowledge to exploit the MS/MS capability of triple quadrupole mass spectrometers presents a significantly different challenge from setting up qualitative single stage mass spectrometry systems. Evolution of quantitative open access mass spectrometry within a pharmaceutical drug metabolism and pharmacokinetics group, from its beginnings as a single generic system to a series of specialist fully integrated walk-up facilities, is described.

Development of a μ-turbulent flow chromatography focus mode method for drug quantitation in discovery bioanalysis

“…With a larger range of compounds ( Table 5, n = 36), results also indicate mean carryover remains low at approximately 0.09% (range, 0-0.2%), lower than what can be achieved with a binary pump setup with two weakly acidified mobile phases [4]. This has enabled smaller peaks to be accurately quantified and pushes the average system detection limits into the sub-nanogram range, even without spending extra time tuning more sensitive MS/MS parameters ( [20], see Methods section). The low carryover is helped by the low sample injection volume (15 l) which minimises the total mass of both drug and matrix material entering the system.…”

“…At Pfizer within our discovery bioanalytical group, due to the diverse array of compound libraries and a high throughput in vitro ADME screening platform [19,20] that quickly identifies candidate molecules; a significant variety of compounds require a high quality analytical method suitable for further in vivo investigations, lead optimisation and ultimately candidate nomination. Therefore, it is necessary to achieve robust analysis that incorporates analytical sensitivity and accuracy over a wide range of compound physicochemistries.…”

A review of LC–MS techniques and high-throughput approaches used to investigate drug metabolism by cytochrome P450s

“…Single-Stage quadrupole mass spectrometers (SSQMS) as well as triple-stage quadrupole mass spectrometers (TSQMS) are commonly used by the pharmaceutical industry for both qualitative and quantitative studies [9]. Whilst quadrupole mass analysers have the ability to operate in both negative and positive ion modes, specific advantages of SSQMS instruments include low cost and their relatively small size, whilst TSQMS instruments have greater discrimination against chemical background resulting in real gains in selectivity and sensitivity.…”

Mass Spectrometry, Proteomics, Data Mining Strategies and Their Applications in Infectious Disease Research.

“…Mass spectrometers are used in biotechnology for the analysis of proteins, peptides, and oligonucleotides [9]; in pharmaceutical research for drug discovery, combinatorial chemistry, pharmacokinetics, and drug metabolism [10]; in clinical research for neonatal screening, haemoglobin analysis, and drug testing; in environmental sciences for pollutants *Address correspondence to this author at the Ontario Cancer Institute, Toronto Medical Discovery Tower, 101 College Street, Toronto, Ontario M5G 1L7, Canada; Tel: 416-581-7627; Fax. 416-581-7629; E-mail: thomas.kislinger@utoronto.ca (PAHs and PCBs), water quality, and food contamination [11]; and geologically for oil composition determination [12].…”