Use of Accelerator Mass Spectrometry to Measure the Pharmacokinetics and Peripheral Blood Mononuclear Cell Concentrations of Zidovudine

Vuong, Le Thuy; Ruckle, Jon; Blood, Arlin B.; Reid, Michael; Wasnich, Richard D.; Synal, Hans-Arno; Dueker, Stephen R.

doi:10.1002/jps.21160

Cited by 36 publications

(38 citation statements)

References 22 publications

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“…All structural information is, however, lost because samples need to be graphitized before analysis. The method has been used to measure 14 C-labeled AZT in PBMCs (Vuong et al, 2008), but because no separation was performed, the found concentrations were the sum of all AZT metabolites in the PBMCs, including those incorporated in nucleic acids. After isolation and de-phosphorylation of AZT-TP the methodology could, however, be used for the specific quantification of 14 C-labeled AZT-TP in PBMCs (Chen et al, 2009).…”

Section: Separation and Detectionmentioning

confidence: 99%

Mass spectrometry in the quantitative analysis of therapeutic intracellular nucleotide analogs

Jansen

Rosing

Schellens

et al. 2011

Mass Spectrometry Reviews

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Nucleoside analogs are widely used in anti-cancer, anti-(retro)viral, and immunosuppressive therapy. Nucleosides are prodrugs that require intracellular activation to mono-, di-, and finally triphosphates. Monitoring of these intracellular nucleotides is important to understand their pharmacology. The relatively involatile salts and ion-pairing agents traditionally used for the separation of these ionic analytes limit the applicability of mass spectrometry (MS) for detection. Both indirect and direct methods have been developed to circumvent this apparent incompatibility. Indirect methods consist of de-phosphorylation of the nucleotides into nucleosides before the actual analysis. Various direct approaches have been developed, ranging from the use of relatively volatile or very low levels of regular ion-pairing agents, hydrophilic interaction chromatography (HILIC), weak anion-exchange, or porous graphitic carbon columns to capillary electrophoresis and matrix-assisted light desorption--time of flight (MALDI-TOF) MS. In this review we present an overview of the publications describing the quantitative analysis of therapeutic intracellular nucleotide analogs using MS. The focus is on the different approaches for their direct analysis. We conclude that despite the technical hurdles, several useful MS-compatible chromatographic approaches have been developed, enabling the use of the excellent selectivity and sensitivity of MS for the quantitative analysis of intracellular nucleotides.

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Section: Separation and Detectionmentioning

confidence: 99%

Mass spectrometry in the quantitative analysis of therapeutic intracellular nucleotide analogs

Jansen

Rosing

Schellens

et al. 2011

Mass Spectrometry Reviews

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“…AMS is a nuclear physics instrument originally developed for radiocarbon dating that is increasingly being used in drug development. [27][28][29][30] AMS has the attraction of high sensitivity (attograms to zeptograms), thus permitting drug and metabolite blood concentrations to be measured aer low-dose drug administrations. There have been isolated reports on the use of LC/MS to measure parent drug concentration aer microdose administration, 31-33 but for an unknown development drug AMS will always be the superior analytical technique because of its large dynamic range, its ability to quantitate metabolites and not requiring internal standardisation.…”

Section: What Is Microdosing (Human Phase 0 Studies)mentioning

confidence: 99%

Human Microdosing/Phase 0 Studies to Accelerate Drug Development

Garner¹

2014

Human-Based Systems for Translational Research

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There is an urgent need to accelerate the development of new drugs to treat unmet medical needs both in the developed and underdeveloped parts of the world. There is also an urgent need to improve the efficiency of drug development through time and cost reduction because development costs hinder the introduction of new therapies. There are many life-threatening human diseases that still require better therapies including cancer, bacterial and viral infection and lifestyle-associated diseases. The costs of bringing a drug to market are so high that there are very few organisations able to afford to discover, develop and introduce drugs on their own. Estimates of drug development costs vary between US$1.2 and 12.0 billion dollars, making the costs of newly approved drugs very high in order that companies can recover the costs of all the failed drugs in their pipelines. 1,2 It has been estimated that only three out of 10 drugs make a return on their investment and that over 99% of molecules researched by a pharmaceutical company are likely to fail at some point during the development process. 3 Even when a drug enters into RSC Drug Discovery Series No. 41 Human-based Systems for Translational Research Edited by Robert Coleman

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“…Clinical studies of mass balance in human subjects are challenged by limitations in sample collection and the use of isotopes. The use of microdosing studies based on trace radiation doses to evaluate mass balance has been examined (Vuong et al, 2008). Following drug administration, urine and fecal samples were collected and radioactivity was measured in these samples.…”

Section: Mass Balancementioning

confidence: 99%

Microdosing studies using accelerated mass spectrometry as exploratory investigational new drug trials

Bae

Shon

2011

Arch. Pharm. Res.

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Innovative attempts have been made to overcome nonproductivity and high expenditure in the clinical stages of new drug development. Microdosing studies using subpharmacological doses provide early insight into the body's disposition toward candidate compounds, and are innovative exploratory trials that can promote productivity in drug development. Highly sensitive analytical technology is crucial in microdosing studies that employ qualitative and quantitative assays of target materials in humans. Accelerator mass spectrometry (AMS) has facilitated the adoption of a human microdosing study in the early phase of clinical drug development. Results derived from AMS microdosing studies using labeled compounds can provide various types of information for candidate selection, including pharmacokinetic characteristics and metabolic profiles of candidate compounds. The applicability of microdosing studies is currently expanding into absolute bioavailability and mass balance studies. Although it remains uncertain whether microdosing adequately predicts the pharmacokinetics of therapeutic doses, further development of microdosing studies using AMS may benefit the field of new drug development and could pose a new challenge to researchers. The use of advanced technology in candidate selection will contribute to improved productivity and competitiveness in pharmaceutical research and development. The introduction of microdosing studies using AMS in Korea will present a newly applicable method for innovative clinical trials and contribute to development potential in global competition.

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Use of Accelerator Mass Spectrometry to Measure the Pharmacokinetics and Peripheral Blood Mononuclear Cell Concentrations of Zidovudine

Cited by 36 publications

References 22 publications

Mass spectrometry in the quantitative analysis of therapeutic intracellular nucleotide analogs

Mass spectrometry in the quantitative analysis of therapeutic intracellular nucleotide analogs

Human Microdosing/Phase 0 Studies to Accelerate Drug Development

Microdosing studies using accelerated mass spectrometry as exploratory investigational new drug trials

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