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Measurement of 5,10-dideaza-5,6,7,8-tetrahydrofolate (lometrexol) in human plasma and urine by high-performance liquid chromatography

Lookup NU author(s): Professor Steve Wedge, Gordon Taylor, Professor Herbie Newell

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Abstract

Three high-performance liquid chromatographic methods are described for the detection of the novel antifolate anticancer drug (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate (lometrexol): one with fluorometric detection and two with detection by UV absorbance. An assay for plasma lometrexol using UV detection (288 nm) and reversed-phase chromatography was developed, with a quantitation limit of 0.2 mu g/ml and linearity up to 10 mu g/ml. This assay was modified for measurement of lometrexol in urine, with a quantitation limit of 2 mu g/ml and linearity up to 25 mu g/ml. An alternative assay for plasma lometrexol using derivatization and fluorescence detection (excitation at 325 nm. emission at 350 nm) was also developed, which proved twenty-fold more sensitive (quantitation limit of 10 ng/ml) than the UV assay, and which was linear up to 250 ng/ml. The fluorometric method requires sample oxidation with manganese dioxide prior to analysis, and uses ion-pair chromatography with tetramethylammonium hydrogensulphate as an ion-pair reagent. All assays use a similar preliminary solid-phase extraction method (recovery as assessed by UV absorption >73%), with C10-desmethylene lometrexol added for internal standardisation. Each assay is highly reproducible (inter-assay precision in each assay is <10%). Applicability of the fluorescence-based assay to lometrexol in plasma and the UV-based assay to lometrexol in urine is demonstrated by pharmacokinetic studies in patients treated as part of a Phase I clinical evaluation of the drug.

Publication metadata

Author(s): Wedge SR, Laohavinij S, Taylor GA, Newell DR

Publication type: Article

Publication status: Published

Journal: Journal of Chromatography B: Biomedical Sciences and Applications

Year: 1995

Volume: 663

Issue: 2

Pages: 327-335

Print publication date: 01/01/1995

ISSN (print): 1570-0232

ISSN (electronic):

URL: http://dx.doi.org/10.1016/0378-4347(94)00441-7

DOI: 10.1016/0378-4347(94)00441-7

PubMed id: 7735480

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