Sixth International Congress

Drug Therapy in HIV Infection


17-21 November, 2002
Glasgow, UK

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Intracellular metabolism of AZT leads to the production of significant levels of d4T triphosphate in HIV-infected patients

Jacques Grassi, François Becher, Alain Pruvost, Dimitri Schlemmer, Christophe Créminon, Henri Benech*, Cécile Goujard, Jean-François Delfraissy**
Int Cong Drug Therapy HIV 2002 Nov 17-21;6:Abstract No. PL8.3

[ABSTRACT:] Nucleoside reverse transcriptase inhibitors (NRTIs) are anabolised intracellularly to their known corresponding active triphosphate (TP). This intracellular anabolism plays a critical role regarding both their efficacy and toxicity.

Using a newly developed direct LC/MS/MS technique [1,2], able to detect simultaneously the phosphorylated form of several NRTIs, we made the surprising observation that intracellular metabolism of AZT, well known to produce AZT-TP, systematically leads to the formation of d4T-TP, usually resulting of the intracellular anabolism of d4T. This seems strictly restricted to the intracellular anabolism of AZT since analysis of PBMCs from patients with therapy excluding both AZT and d4T never shown d4T-TP and, significant amount of d4T were not detected in the plasma of AZT-treated patients. Intracellular d4T-TP concentrations measured in AZT-treated patients represent between 3% and 37% of the corresponding AZT-TP concentrations and are in the lower range of d4T-TP concentrations measured in d4T-treated patients3, indicating that d4T-TP could participate to the antiretroviral activity and/or toxicity of AZT. This observation, also supported by in vitro experiments, brings a new light on the cross resistance observed between AZT and d4T.

Presenting author: Jacques Grassi

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* CEA, Pharmacology and Immunology Unit, DSV/DRM, 91191 Gif-sur-Yvette Cedex

** Internal Medicine Unit, University Hospital of Bicêtre, Kremlin-Bicêtre, France

References

1 Pruvost A, et al. "Direct determination of phosphorylated intracellular anabolites of stavudine (d4T) by liquid chromatography/tandem mass spectrometry", Rapid Commun Mass Spectrom 2001;15(16):1401-8.

2 Becher F, et al. "Development of a direct assay for measuring intracellular AZT triphosphate in humans peripheral blood mononuclear cells", Anal Chem 2002 Aug 15;74(16):4220-7.

3 Becher F, et al. "Monitoring Intracellular Triphosphorylated Anabolites of Didanosine EC (ddI) and Stavudine (d4T): Results of a Pilot Clinical Study in HIV-Infected Patients", 9th CROI, Seattle, 2002. Abstract 452-W

2002-11-17
PL8-4

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