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Antimicrobial Agents and Chemotherapy, February 2001, p. 577-582, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.577-582.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Influence of Prior Exposure to Zidovudine on Stavudine Phosphorylation In Vivo and Ex Vivo

P. G. Hoggard,1,* S. D. Sales,1,2 D. Phiboonbanakit,1 J. Lloyd,1 B. A. Maher,1 S. H. Khoo,1 E. Wilkins,3 P. Carey,4 C. A. Hart,2 and D. J. Back1

Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom L69 3GE1; Department of Medical Microbiology, University of Liverpool, Liverpool, United Kingdom L69 3GA2; and Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital, Crumpsall, Manchester4; and Department of Genitourinary Medicine, Royal Liverpool University Hospital, Liverpool,3 United Kingdom

Received 11 May 2000/Returned for modification 6 September 2000/Accepted 25 October 2000

Intracellular phosphorylation of stavudine (d4T) and zidovudine (ZDV) was investigated in peripheral blood mononuclear cells (PBMCs) isolated from ZDV-naive and ZDV-experienced human immunodeficiency virus (HIV)-positive patients. An in vivo study measured the amount of d4T triphosphate (d4TTP), while an ex vivo study assessed the capacity of cells to phosphorylate added d4T. Endogenous dTTP was also measured. d4TTP and dTTP were determined in vivo using a reverse transcriptase chain termination assay. In ex vivo studies, d4T (1 µM) was incubated in resting and phytohemagglutinin-stimulated (10 µg ml-1; 72 h) PBMCs for 24 h. After washing and methanol extraction, radiolabeled anabolites were detected by high-performance liquid chromatography. d4TTP reached its highest level 2 to 4 h after dosing (0.21 ± 0.14 pmol/106 cells; n = 27 [mean ± standard deviation]). Comparison of ZDV-naive and ZDV-experienced individuals showed no significant difference in levels of d4TTP (ZDV naive, 0.23 ± 0.17 pmol/106 cells [n = 7] versus ZDV experienced, 0.20 ± 0.14 pmol/106 cells [n = 20]; P = 0.473) or the d4TTP/dTTP ratio (0.14 ± 0.12 [n = 7] and 0.10 ± 0.08 [n = 20], respectively; p = 0.391). Ex vivo data demonstrated no significant difference in the formation of d4TTP or total d4T phosphates in naive and experienced patients (0.086 ± 0.055 pmol/106 cells in ZDV-naive patients [n = 17] versus 0.081 ± 0.038 pmol/106 cells in ZDV-experienced patients [n = 22]; P = 0.767). The ability of HIV-infected patients to phosphorylate d4T in vivo and ex vivo was unchanged with increasing exposure to ZDV.

* Corresponding author. Mailing address: Department of Pharmacology and Therapeutics, University of Liverpool, New Medical Building, Ashton St., Liverpool, United Kingdom L69 3GE. Phone: 0151 794-5565. Fax: 0151 794-5540. E-mail: patrick{at}liv.ac.uk.

Antimicrobial Agents and Chemotherapy, February 2001, p. 577-582, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.577-582.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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