DESIGN AND OBJECTIVE: It has been previously shown that zidovudine (ZDV) and its phosphorylated metabolites can be chemically reduced into the corresponding stavudine (d4T) forms in solution. The aim of this study was to search for intracellular d4T-triphosphate (TP) in patients receiving ZDV therapy as part of highly active antiretroviral therapy and to examine the ratio of concentrations of d4T-TP : ZDV-TP in these patients. METHODS: Seven ml of blood were sampled between 0.5 and 13.7 h after the last ZDV dosing in 31 patients. Peripheral blood mononuclear cells (PBMC) were separated using Vacutainer CPT tubes. Intracellular d4T-TP and ZDV-TP concentrations were determined by a newly developed high performance liquid chromatography/tandem mass spectrometry method. RESULTS: Intracellular d4T-TP was found in all ZDV-treated patients. d4T-TP concentrations ranged between 3 and 38.5 fmol/1 x 10 cells and represented between 0.03 and 0.37 of the corresponding ZDV-TP concentrations. These d4T-TP concentrations are in the lower range of those measured in d4T-treated patients. The intracellular transformation of ZDV into d4T-TP was also observed during experiments in cells cultured in the presence of ZDV. d4T-TP was never detected in PBMC from patients treated with neither ZDV nor d4T. CONCLUSION: Significant levels of d4T-TP can be measured in PBMC from patients receiving ZDV therapy. This observation sheds new light on the cross resistance observed between ZDV and d4T and indicates that, in patients treated with ZDV, d4T-TP could participate in the antiretroviral activity and/or toxicity of the drug.
DESIGN AND OBJECTIVE: It has been previously shown that zidovudine (ZDV) and its phosphorylated metabolites can be chemically reduced into the corresponding stavudine (d4T) forms in solution. The aim of this study was to search for intracellular d4T-triphosphate (TP) in patients receiving ZDV therapy as part of highly active antiretroviral therapy and to examine the ratio of concentrations of d4T-TP : ZDV-TP in these patients. METHODS: Seven ml of blood were sampled between 0.5 and 13.7 h after the last ZDV dosing in 31 patients. Peripheral blood mononuclear cells (PBMC) were separated using Vacutainer CPT tubes. Intracellular d4T-TP and ZDV-TP concentrations were determined by a newly developed high performance liquid chromatography/tandem mass spectrometry method. RESULTS: Intracellular d4T-TP was found in all ZDV-treated patients. d4T-TP concentrations ranged between 3 and 38.5 fmol/1 x 10 cells and represented between 0.03 and 0.37 of the corresponding ZDV-TP concentrations. These d4T-TP concentrations are in the lower range of those measured in d4T-treated patients. The intracellular transformation of ZDV into d4T-TP was also observed during experiments in cells cultured in the presence of ZDV. d4T-TP was never detected in PBMC from patients treated with neither ZDV nor d4T. CONCLUSION: Significant levels of d4T-TP can be measured in PBMC from patients receiving ZDV therapy. This observation sheds new light on the cross resistance observed between ZDV and d4T and indicates that, in patients treated with ZDV, d4T-TP could participate in the antiretroviral activity and/or toxicity of the drug.
Authors: Delia Susan-Resiga; Alice T Bentley; Matthew D Lynx; Darcy D LaClair; Edward E McKee Journal: Antimicrob Agents Chemother Date: 2007-01-12 Impact factor: 5.191
Authors: Anthony R Vortherms; Robert P Doyle; Dayuan Gao; Olivia Debrah; Patrick J Sinko Journal: Nucleosides Nucleotides Nucleic Acids Date: 2008-02 Impact factor: 1.381
Authors: Andrea Cossarizza; Hyun-Dong Chang; Andreas Radbruch; Andreas Acs; Dieter Adam; Sabine Adam-Klages; William W Agace; Nima Aghaeepour; Mübeccel Akdis; Matthieu Allez; Larissa Nogueira Almeida; Giorgia Alvisi; Graham Anderson; Immanuel Andrä; Francesco Annunziato; Achille Anselmo; Petra Bacher; Cosima T Baldari; Sudipto Bari; Vincenzo Barnaba; Joana Barros-Martins; Luca Battistini; Wolfgang Bauer; Sabine Baumgart; Nicole Baumgarth; Dirk Baumjohann; Bianka Baying; Mary Bebawy; Burkhard Becher; Wolfgang Beisker; Vladimir Benes; Rudi Beyaert; Alfonso Blanco; Dominic A Boardman; Christian Bogdan; Jessica G Borger; Giovanna Borsellino; Philip E Boulais; Jolene A Bradford; Dirk Brenner; Ryan R Brinkman; Anna E S Brooks; Dirk H Busch; Martin Büscher; Timothy P Bushnell; Federica Calzetti; Garth Cameron; Ilenia Cammarata; Xuetao Cao; Susanna L Cardell; Stefano Casola; Marco A Cassatella; Andrea Cavani; Antonio Celada; Lucienne Chatenoud; Pratip K Chattopadhyay; Sue Chow; Eleni Christakou; Luka Čičin-Šain; Mario Clerici; Federico S Colombo; Laura Cook; Anne Cooke; Andrea M Cooper; Alexandra J Corbett; Antonio Cosma; Lorenzo Cosmi; Pierre G Coulie; Ana Cumano; Ljiljana Cvetkovic; Van Duc Dang; Chantip Dang-Heine; Martin S Davey; Derek Davies; Sara De Biasi; Genny Del Zotto; Gelo Victoriano Dela Cruz; Michael Delacher; Silvia Della Bella; Paolo Dellabona; Günnur Deniz; Mark Dessing; James P Di Santo; Andreas Diefenbach; Francesco Dieli; Andreas Dolf; Thomas Dörner; Regine J Dress; Diana Dudziak; Michael Dustin; Charles-Antoine Dutertre; Friederike Ebner; Sidonia B G Eckle; Matthias Edinger; Pascale Eede; Götz R A Ehrhardt; Marcus Eich; Pablo Engel; Britta Engelhardt; Anna Erdei; Charlotte Esser; Bart Everts; Maximilien Evrard; Christine S Falk; Todd A Fehniger; Mar Felipo-Benavent; Helen Ferry; Markus Feuerer; Andrew Filby; Kata Filkor; Simon Fillatreau; Marie Follo; Irmgard Förster; John Foster; Gemma A Foulds; Britta Frehse; Paul S Frenette; Stefan Frischbutter; Wolfgang Fritzsche; 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Alicia Martínez-Romero; Glòria Martrus; Ivana Marventano; Wlodzimierz Maslinski; Giuseppe Matarese; Anna Vittoria Mattioli; Christian Maueröder; Alessio Mazzoni; James McCluskey; Mairi McGrath; Helen M McGuire; Iain B McInnes; Henrik E Mei; Fritz Melchers; Susanne Melzer; Dirk Mielenz; Stephen D Miller; Kingston H G Mills; Hans Minderman; Jenny Mjösberg; Jonni Moore; Barry Moran; Lorenzo Moretta; Tim R Mosmann; Susann Müller; Gabriele Multhoff; Luis Enrique Muñoz; Christian Münz; Toshinori Nakayama; Milena Nasi; Katrin Neumann; Lai Guan Ng; Antonia Niedobitek; Sussan Nourshargh; Gabriel Núñez; José-Enrique O'Connor; Aaron Ochel; Anna Oja; Diana Ordonez; Alberto Orfao; Eva Orlowski-Oliver; Wenjun Ouyang; Annette Oxenius; Raghavendra Palankar; Isabel Panse; Kovit Pattanapanyasat; Malte Paulsen; Dinko Pavlinic; Livius Penter; Pärt Peterson; Christian Peth; Jordi Petriz; Federica Piancone; Winfried F Pickl; Silvia Piconese; Marcello Pinti; A Graham Pockley; Malgorzata Justyna Podolska; Zhiyong Poon; Katharina Pracht; Immo Prinz; Carlo E M Pucillo; Sally A Quataert; Linda Quatrini; Kylie M Quinn; Helena Radbruch; Tim R D J Radstake; Susann Rahmig; Hans-Peter Rahn; Bartek Rajwa; Gevitha Ravichandran; Yotam Raz; Jonathan A Rebhahn; Diether Recktenwald; Dorothea Reimer; Caetano Reis e Sousa; Ester B M Remmerswaal; Lisa Richter; Laura G Rico; Andy Riddell; Aja M Rieger; J Paul Robinson; Chiara Romagnani; Anna Rubartelli; Jürgen Ruland; Armin Saalmüller; Yvan Saeys; Takashi Saito; Shimon Sakaguchi; Francisco Sala-de-Oyanguren; Yvonne Samstag; Sharon Sanderson; Inga Sandrock; Angela Santoni; Ramon Bellmàs Sanz; Marina Saresella; Catherine Sautes-Fridman; Birgit Sawitzki; Linda Schadt; Alexander Scheffold; Hans U Scherer; Matthias Schiemann; Frank A Schildberg; Esther Schimisky; Andreas Schlitzer; Josephine Schlosser; Stephan Schmid; Steffen Schmitt; Kilian Schober; Daniel Schraivogel; Wolfgang Schuh; Thomas Schüler; Reiner Schulte; Axel Ronald Schulz; Sebastian R Schulz; Cristiano Scottá; 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Annika Wiedemann; Jürgen Wienands; Anneke Wilharm; Robert John Wilkinson; Gerald Willimsky; James B Wing; Rieke Winkelmann; Thomas H Winkler; Oliver F Wirz; Alicia Wong; Peter Wurst; Jennie H M Yang; Juhao Yang; Maria Yazdanbakhsh; Liping Yu; Alice Yue; Hanlin Zhang; Yi Zhao; Susanne Maria Ziegler; Christina Zielinski; Jakob Zimmermann; Arturo Zychlinsky Journal: Eur J Immunol Date: 2019-10 Impact factor: 6.688