Journal article
Quantitative determination of a potent geranylgeranyl diphosphate synthase inhibitor using LC–MS/MS: Derivatization and application
Journal of pharmaceutical and biomedical analysis, Vol.153, pp.22-28
05/10/2018
DOI: 10.1016/j.jpba.2018.02.010
PMCID: PMC5857472
PMID: 29455093
Abstract
•A LC–MS/MS for quantitation of VSW1198 in mouse plasma and tissues.•Highly sensitive and stable derivatized compounds were analyzed by LC–MS/MS.•This approach could be applied to other structurally similar bisphosphonates.
An isomeric mixture of homogeranyl/homoneryl triazole bisphosphonates (VSW1198) has previously been shown to be a potent inhibitor of geranylgeranyl diphosphate (GGDP) synthase (GGDPS) and of therapeutic interest for the treatment of multiple myeloma. We have developed and validated a selective and sensitive liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) method for the simultaneous quantitation of both the E- and Z- isomers of VSW1198 in cell culture media, mouse plasma and tissues. VSW1198 and internal standard are extracted from the bio-matrices by solid-phase extraction, followed by derivatization using trimethylsilyldiazomethane. The chromatographic separation of analytes was achieved on a Phenomenex Gemini NX column (150 mm * 2.0 mm, 5 μ) with gradient elution using 0.1% acetic acid and methanol/acetonitrile (1:1) as the mobile phase at a flow rate of 0.2 mL/min. Derivatized analytes were ionized with an electrospray ionization source in positive multiple reaction monitoring (MRM) mode and quantitated using MS/MS. The MS/MS response was linear over the concentration range from 0.38–1500 and 0.13–500 ng/mL for the E- and Z-isomers, respectively. The within- and between-day precision (relative standard deviation, % RSD) and accuracy were within the acceptable limits per FDA guidelines. The validated method was used for quantitative determination of the compounds in preclinical studies focused on the development of VSW1198 as a novel anti-cancer agent.
Details
- Title: Subtitle
- Quantitative determination of a potent geranylgeranyl diphosphate synthase inhibitor using LC–MS/MS: Derivatization and application
- Creators
- Yashpal S Chhonker - Department of Pharmacy Practice, University of Nebraska Medical Center, Omaha, NE 68198, United StatesStaci L Haney - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United StatesRobert A Matthiesen - Department of Chemistry, University of Iowa, Iowa City, IA 52242, United StatesDavid F Wiemer - Department of Chemistry, University of Iowa, Iowa City, IA 52242, United StatesSarah A Holstein - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United StatesDaryl J Murry - Department of Pharmacy Practice, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Resource Type
- Journal article
- Publication Details
- Journal of pharmaceutical and biomedical analysis, Vol.153, pp.22-28
- DOI
- 10.1016/j.jpba.2018.02.010
- PMID
- 29455093
- PMCID
- PMC5857472
- NLM abbreviation
- J Pharm Biomed Anal
- ISSN
- 0731-7085
- eISSN
- 1873-264X
- Publisher
- Elsevier B.V
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R01CA-172070; DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust; DOI: 10.13039/100006518, name: University of Nebraska Medical Center; DOI: 10.13039/100000054, name: National Cancer Institute
- Language
- English
- Date published
- 05/10/2018
- Academic Unit
- Neuroscience and Pharmacology; Chemistry; Holden Comprehensive Cancer Center
- Record Identifier
- 9984216671402771
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