HPLC-API/MS/MS: a powerful tool for integrating drug metabolism into the drug discovery process

Korfmacher, Walter A.; Cox, Kathleen; Bryant, Matthew; Veals, J.; Ng, Kwokei; Lin, Chin‐Chung; Watkins, Robert E. J.

doi:10.1016/s1359-6446(97)01121-5

Cited by 99 publications

(92 citation statements)

References 12 publications

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“…The sensitivity and selectivity of LC/MS, in addition to the opportunity it provides for rapid method development, have made it a particularly powerful technique to support high-throughput DMPK approaches (28,29). LC/MS is now the method of choice to provide both qualitative and quantitative information in place of the more traditional high-pressure LC methods with UV or fluorescence detection (30). Multiple reaction monitoring done on a triple quadrupole instrument allows the detection of several compounds simultaneously and is the Cassette Dosing in Anticancer Drug Discovery enabling technology for the multiple compound pharmacokinetic approaches that will be discussed below.…”

Section: Dmpk In Drug Discoverymentioning

confidence: 99%

The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery

Smith

Raynaud

Workman

2007

Molecular Cancer Therapeutics

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Pharmacokinetic evaluation is an essential component of drug discovery and should be conducted early in the process so that those compounds with the best chance of success are prioritized and progressed. However, pharmacokinetic analysis has become a serious bottleneck during the 'hit-to-lead' and lead optimization phases due to the availability of new targets and the large numbers of compounds resulting from advances in synthesis and screening technologies. Cassette dosing, which involves the simultaneous administration of several compounds to a single animal followed by rapid sample analysis by liquid chromatography/tandem mass spectrometry, was developed to increase the throughput of in vivo pharmacokinetic screening. Although cassette dosing is advantageous in terms of resources and throughput, there are possible complications associated with this approach, such as the potential for compound interactions. Following an overview of the cassette dosing literature, this article focuses on the application of the technique in anticancer drug discovery. Specific examples are discussed, including the evaluation of cassette dosing to assess pharmacokinetic properties in the development of cyclin-dependent kinase and heat shock protein 90 inhibitors. Subject to critical analysis and validation in each case, the use of cassette dosing is recommended in appropriate chemical series to enhance the efficiency of drug discovery and reduce animal usage. [Mol Cancer Ther 2007;6(2):428 -40]

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Section: Dmpk In Drug Discoverymentioning

confidence: 99%

The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery

Smith

Raynaud

Workman

2007

Molecular Cancer Therapeutics

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“…For drug discovery, protein precipitation (PP) is the most common sample preparation procedure; liquid-liquid extraction (LLE) and solid-phase extraction (SPE) have also been reported as preparation techniques for plasma samples (1,3,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). PP is the simplest approach because it requires no method development, and it removes the majority of the protein from the sample.…”

Section: Sample Preparationmentioning

confidence: 99%

Rapid LC/MS/MS Method Development for Drug Discovery

Xu¹,

Lan²,

Korfmacher³

2005

Anal. Chem.

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“…When coupled with on-line HPLC, the technique is extremely robust, rapid, sensitive, and easily automated (1,2,(8)(9)(10)(11). Not surprisingly, LC/MS and LC/MS/MS have become the methods of choice for pharmacokinetic studies, yielding concentration versus time data for drug compounds from in vivo samples such as plasma (1,2).…”

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confidence: 99%