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.
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.
Lefebvre
Isabelle
I
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-UMI-UMII, Université Montpellier II, case courrier 1705, place Eugène Bataillon, 34095 Montpellier cedex 05, France. isabelle.tournier@univ-montp2.fr
Beltran
Thierry
T
Peyrottes
Suzanne
S
Périgaud
Christian
C
D001688:Biological Products / Q000378:metabolism*; D002853:Chromatography, Liquid; D054306:Dideoxynucleotides / Q000032:analysis* / Q000378:metabolism*; D004355:Drug Stability; D013058:Mass Spectrometry; D011355:Prodrugs / Q000032:analysis* / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D052616:Solid Phase Extraction; D012995:Solubility; D013942:Thymine Nucleotides / Q000032:analysis* / Q000378:metabolism*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism
D001688:Biological Products; D054306:Dideoxynucleotides; D011355:Prodrugs; D013942:Thymine Nucleotides; C057287:3'-azido-3'-deoxythymidine 5'phosphate; D015215:Zidovudine