The Use of On-line and Off-line Chromatographic Extraction Techniques coupled with Mass Spectrometry for Support of In Vivo and In Vitro Assays in Drug Discovery

Masucci, John A.; Caldwell, Gary W.; Jones, Walter W.; Juzwin, Stephen J.; Sasso, Patrick J.; Evangelisto, Mary

doi:10.2174/1568026013394985

Cited by 8 publications

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MS Applications in Support of Medicinal Chemistry Sciences

Honing¹,

Ingelse²,

Pramanik³

2013

Mass Spectrometry for Drug Discovery and Drug Development

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In the drug discovery process, medicinal chemistry plays a crucial role in the optimal design and synthesis (production) of new chemical entities (NCEs) or new biological entities (NBEs); this is true for a single entity as well as a complete compound library. A key requirement in this field of science is the optimization of both the chemical and the biological properties of these potential drug-like compounds. Important criteria are the design of efficient synthesis routes, the balancing of the physical chemical properties with optimal in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) processes, and a profound understanding of the pharmacodynamics in the appropriate pharmacological models. In the lead optimization stage, an important step is scaling up the synthesis route as needed for the execution of toxicology studies and the screening of suitable drug formulations. In summary, medicinal chemistry support includes participating in a large variety of activities and decision making processes that play a key role in the search for either a "first in class" new drug or a "best in class" new drug [1].These "drug discovery" processes are continuously under pressure, as the research and development (R&D) costs continue to increase and more data are requested before new drug candidates are taken into (pre-)clinical development. Hence, the choice of "targeted" high-throughput screening (HTS) libraries, the process of hit appraisal, and the understanding of target-ligand interactions can be considered the starting points for a new drug discovery program [2]. Next, the main focus is on the discovery of a lead compound; typically, this is a compound showing promising data regarding target affinity, reasonable efficacy in cellular models, good physical chemical parameters (i.e., a "drug-like" compound), and acceptable oral bioavailability in Mass Spectrometry for Drug Discovery and Drug Development, First Edition. Edited by Walter A. Korfmacher.

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MS Applications in Support of Medicinal Chemistry Sciences

Honing¹,

Ingelse²,

Pramanik³

2013

Mass Spectrometry for Drug Discovery and Drug Development

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Quantification of sifuvirtide in monkey plasma by an on‐line solid‐phase extraction procedure combined with liquid chromatography/electrospray ionization tandem mass spectrometry

Dai

Song

Dou³

et al. 2005

Rapid Comm Mass Spectrometry

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A simple, automated and rapid method has been developed for the determination of a novel antiviral peptide sifuvirtide in monkey plasma. Raw plasma samples were directly loaded onto an on-line solid-phase extraction (SPE) column, which removes the time-consuming and laborious sample pretreatment. Following a timed valve-switching event, the analyte was eluted on-line to a reversed-phase high-performance liquid chromatography (RP-HPLC) column and subsequently introduced into a linear ion trap mass spectrometer, LTQ-MS, via an electrospray ionization (ESI) interface. The multiply charged peptides were specified and quantitatively analyzed using selective reaction monitoring (SRM). A highly pure four iodine-sifuvirtide was synthesized using an optimized iodogen method and proved to be a suitable internal standard (IS). A single analysis run takes about 18 min. Validation of the method demonstrated that the linear calibration curves covered the range of 4.88-5000 ng/mL, and the correlation coefficients were above 0.9923. The limit of detection (LOD) with the signal-to-noise (S/N) ratio higher than 12 was calculated as 1.22 ng/mL. The intra- and inter-batch precisions were less than 12.7% and 9.1%, and the mean accuracy ranged from -5.2% to 3.6%, respectively. Any carry-over effect from the system was negligible. In a pharmacokinetic (PK) study of sifuvirtide after a single intravenous or subcutaneous dose in monkeys, the on-line SPE-LC/MS/MS system was successfully utilized to determine hundreds of samples with only one extraction column, which indicated the feasibility and the reliability of this method for application in preclinical and clinical PK studies of peptide drugs.

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A novel on‐line solid‐phase extraction approach integrated with a monolithic column and tandem mass spectrometry for direct plasma analysis of multiple drugs and metabolites

Zang

Luo

Song

et al. 2005

Rapid Comm Mass Spectrometry

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An on-line solid-phase extraction liquid chromatography/tandem mass spectrometry (SPE LC/MS/MS) assay using a newly developed SPE column and a monolithic column was developed and validated for direct analysis of plasma samples containing multiple analytes. This assay was developed in an effort to increase bioanalysis throughput and reduce the complexity of on-line SPE LC/MS/MS systems. A simple column-switching configuration that requires only one six-port valve and one HPLC pumping system was employed for on-line plasma sample preparation and subsequent gradient chromatographic separation. The resulting analytical method couples the desired sensitivity with ease of use. The method was found to perform satisfactorily for direct plasma analysis with respect to assay linearity, specificity, sensitivity, precision, accuracy, carryover, and short-term stability of an eight-analyte mixture in plasma. A gradient LC condition was applied to separate the eight analytes that cannot be distinctly differentiated by MS/MS. With a run time for every injection of 2.8 min, a minimum of 300 direct plasma injections were made on one on-line SPE column without noticeable changes in system performance. Due to the ruggedness and simplicity of this system, generic methods can be easily developed and applied to analyze a wide variety of compounds in a high-throughput manner without laborious off-line sample preparation.

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The Use of On-line and Off-line Chromatographic Extraction Techniques coupled with Mass Spectrometry for Support of In Vivo and In Vitro Assays in Drug Discovery

Cited by 8 publications

References 0 publications

MS Applications in Support of Medicinal Chemistry Sciences

MS Applications in Support of Medicinal Chemistry Sciences

Quantification of sifuvirtide in monkey plasma by an on‐line solid‐phase extraction procedure combined with liquid chromatography/electrospray ionization tandem mass spectrometry

A novel on‐line solid‐phase extraction approach integrated with a monolithic column and tandem mass spectrometry for direct plasma analysis of multiple drugs and metabolites

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