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

Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-UMI-UMII, Université Montpellier II, case courrier 1705, place Eugène Bataillon, 34095 Montpellier cedex 05, France.
Biomedical Chromatography (Impact Factor: 1.72). 11/2009; 23(11):1160-8. DOI: 10.1002/bmc.1238
Source: PubMed


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.

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