Linked Life Data

15866500

Source:http://linkedlifedata.com/resource/pubmed/id/15866500

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2005-5-3
pubmed:abstractText
A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma 2'-deoxyuridine (UdR). It involves a plasma clean-up step with strong anion-exchange solid-phase extraction (SAX-SPE) followed by HPLC separation and atmospheric pressure chemical ionization mass spectrometry detection (APCI-MS) in a selected-ion monitoring (SIM) mode. The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct [M+HCOO]- at m/z 273. Retention times were 7.5 and 12.5 min for 2'-deoxyuridine and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively. Peak area ratios of 2'-deoxyuridine to IS were used for regression analysis of the calibration curve. The latter was linear from 5 to 400 nmol/l using 1 ml sample volume of plasma. The average recovery was 81.5% and 78.6% for 2'-deoxyuridine and 5-iodo-deoxyuridine, respectively. The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma 2'-deoxyuridine concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new fluoropyrimidine analogue capecitabine (N4-pentoxycarbonyl-5'-5-fluorocytidine) have shown that plasma 2'-deoxyuridine was significantly elevated after 1 week of treatment, consistent with inhibition of thymidylate synthase (TS). These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to TS inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of capecitabine or other TS inhibitors in clinical trials. Marked differences of plasma 2'-deoxyuridine between human and rodents have also been confirmed. In conclusion, the LC-MS method developed is simple, highly selective and sensitive and permits pharmacodynamic studies of TS inhibitors in several species.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1570-0232
pubmed:author
pubmed:issnType
Print
pubmed:day
5
pubmed:volume
820
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
121-30
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Rapid quantitation of plasma 2'-deoxyuridine by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients.
pubmed:affiliation
Department of Pharmacology, Faculty of Medicine, Institute for Biomedical Research, School of Medical Sciences, University of Sydney, NSW 2006, Australia.
pubmed:publicationType
Journal Article, Validation Studies