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Decomposition of 3′‐azido‐2′,3′‐dideoxythymidine 5′‐monophosphate (AZTMP) prodrugs in biological media studied by on‐line solid‐phase extraction coupled to liquid chromatography mass spectrometry
Author(s) -
Lefebvre Isabelle,
Beltran Thierry,
Peyrottes Suzanne,
Périgaud Christian
Publication year - 2009
Publication title -
biomedical chromatography
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.4
H-Index - 65
eISSN - 1099-0801
pISSN - 0269-3879
DOI - 10.1002/bmc.1238
Subject(s) - chemistry , chromatography , prodrug , lipophilicity , mass spectrometry , extraction (chemistry) , solid phase extraction , stereochemistry , biochemistry
Using a column‐switching HPLC method previously described, we studied the behavior of some mononucleotide prodrugs (pronucleotides) of 3′‐azido‐2′,3′‐dideoxythymidine in various biological media. From UV data, this method allowed quantification of transient metabolites resulting from prodrug bioconversion. The kinetic data related to the successive steps were calculated according to pseudo‐first‐order kinetic models and optimized using mono‐ or poly‐exponential regressions. Various metabolites were identified by co‐injection with authentic samples and/or ESI‐MS coupling. The results led us to propose, for each considered pronucleotide, a global decomposition pathway ending in the selective delivery of the corresponding mononucleotide. Associated to the determination of other parameters (lipophilicity, aqueous solubility), the present study contributes to the search of suitable pharmacological properties for further in vivo evaluations. Copyright © 2009 John Wiley & Sons, Ltd.