Rapid LC/MS/MS Method Development for Drug Discovery

Xu, Xiao‐Ying; Lan, Jing; Korfmacher, Walter A.

doi:10.1021/ac053476f

Cited by 35 publications

(30 citation statements)

References 22 publications

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“…Since no blank matrix was available we have checked the matrix effect with addition of standards to urine, as a biological matrix. 20 No significant matrix effect was detected (Fig. 3(D) and (E)).…”

Section: Linear Range and Limit Of Quantitationmentioning

confidence: 88%

Study of transaldolase deficiency in urine samples by capillary LC‐MS/MS

et al. 2006

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Transaldolase (TAL) is a key enzyme of the pentose phosphate pathway (PPP). TAL deficiency is a newly recognized cause of liver cirrhosis. We have developed an ion-pair LC separation combined with negative ion electrospray MS/MS detection method to assess PPP metabolites in urine samples from TAL-deficient mice. Sedoheptulose 7-phosphate (S7P), C5-polyols D-arabitol and D-ribitol, and 6-phosphogluconate (6PG) levels were markedly increased in urine of TALdeficient mice with respect to those of wild-type and heterozygote littermates. The detection limits of S7P, D-arabitol, and 6PG were 0.15 ± 0.015 pmol, 3.5 ± 0.41 pmol, and 0.61 ± 0.055 pmol, respectively. The limit of quantitation was 0.4 ± 0.024 nmol/ml for S7P, 1.6 ± 0.11 nmol/ml for 6PG and 10 ± 0.7 nmol/ml for D-arabitol. Additional metabolites,

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Section: Linear Range and Limit Of Quantitationmentioning

confidence: 88%

Study of transaldolase deficiency in urine samples by capillary LC‐MS/MS

et al. 2006

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“…Currently, one has to first do MS/MS method development when performing quantitative analysis using the SRM procedure. [3,5,7,8,14,15] While MS/MS method development typically is neither difficult nor time-consuming when working on one analyte, it can be a challenge when one is faced with the task of assaying 100-200 NCEs per week for an in vitro assay (e.g. metabolic stability assay) or developing a method for assaying multiple components in a single sample.…”

Section: Hrmsmentioning

confidence: 99%

It is time for a paradigm shift in drug discovery bioanalysis: from SRM to HRMS

et al. 2011

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It can be argued that the last true paradigm shift in the bioanalytical (BA) arena was the shift from high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection to HPLC with tandem mass spectrometry (MS/MS) detection after the commercialization of the triple quadrupole mass spectrometer in the 1990s. HPLC-MS/MS analysis based on selected reaction monitoring (SRM) has become the gold standard for BA assays and is used by all the major pharmaceutical companies for the quantitative analysis of new drug entities (NCEs) as part of the new drug discovery and development process. While LC-MS/MS continues to be the best tool for drug discovery bioanalysis, a new paradigm involving high-resolution mass spectrometry (HRMS) and ultrahigh-pressure liquid chromatography (uHPLC) is starting to make inroads into the pharmaceutical industry. The ability to collect full scan spectra, with excellent mass accuracy, mass resolution, 10-250 ms scan speeds and no NCE-related MS parameter optimization, makes the uHPLC-HRMS techniques suitable for quantitative analysis of NCEs while preserving maximum qualitative information about other drug-related and endogenous components such as metabolites, degradants, biomarkers and formulation materials. In this perspective article, we provide some insight into the evolution of the hybrid quadrupole-time-of-flight (Qq-TOF) mass spectrometer and propose some of the desirable specifications that such HRMS systems should have to be integrated into the drug discovery bioanalytical workflow for performing integrated qualitative and quantitative bioanalysis of drugs and related components.

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“…implemented in recent years [24,25]. The popularity of off-line sample processing in batch-mode has dramatically improved the throughput of this ratelimiting step.…”

Section: Sample Preparation Using An Off-line Approachmentioning

confidence: 99%

“…Due to its ease of use and speed, PPT is one of the most common approaches in sample preparation in early drug discovery [25]. While PPT is fast, easy-toapply, and applicable to a broad class of small molecules, it also suffers from SAMPLE PREPARATION USING AN OFF-LINE APPROACH several disadvantages.…”

Section: Pptmentioning

confidence: 99%