title: Concentrations of zidovudine- and lamivudine-triphosphate according to cell type in HIV-seronegative adults.
abstract: BACKGROUND
  Concentrations of zidovudine (ZDV)- and lamivudine (3TC)-triphosphates (TP) have been quantified in unfractionated peripheral blood mononuclear cells (PBMC) from HIV+ patients. The objective of this study was to determine whether concentrations of ZDV-TP and 3TC-TP in PBMC reflect the concentrations within CD4 T cells in HIV-seronegative adults.
  
  
  METHODS
  Volunteers had taken 300 mg of ZDV plus 150 mg of 3TC twice daily for > or = 7 days. Blood (60 mL) was collected 2 or 5 h post observed dose. PBMC were processed into three cell fractions using CD4 magnetic immunobeads: CD4-purified cells; unfractionated PBMC; and CD4-depleted PBMC. TP were determined in each cell fraction with liquid chromatography-mass spectrometry and compared across cell types by non-parametric analyses.
  
  
  RESULTS
  Six males and two females participated. The median (range) percentage of CD4 T cells (CD4%) in each fraction were: CD4-purified, 99%; unfractionated, 63% (range, 53-70); and CD4-depleted, 14% (range, 4-29). Corresponding median (range) ZDV-TP concentrations were 8.0 (5.3-10.3), 26.5 (12.9-42.2), and 34.2 (16.4-52.2) fmol/1 x 10 cells (Friedman P = 0.0008). The 3TC-TP values were 4.6 (2.3-6.7), 4.8 (3.5-8.8), and 6.8 (4.0-13.1) pmol//1 x 10 cells (Friedman P = 0.01). In mixed model analyses: ZDV-TP (fmol/1 x 10 cells) = 42-0.32 (CD4%); P < 0.001 and 3TC-TP (pmol/1 x 10 cells) = 7.3-0.03(CD4%); P = 0.003.
  
  
  CONCLUSIONS
  In HIV-seronegative volunteers, 3TC-TP concentrations in PBMC reflected the concentrations within CD4 T cells, but ZDV-TP concentrations were more than 70% lower in CD4 T cells than in PBMC. Thus, TP concentrations differ according to cell type in vivo with corresponding efficacy and toxicity implications for cells with low or high triphosphates.
authors.affiliation: University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Peter.anderson@uchsc.edu
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Zheng
authors.forename: Tracy
authors.initials: T
authors.lastname: King
authors.forename: Lane R
authors.initials: LR
authors.lastname: Bushman
authors.forename: Julie
authors.initials: J
authors.lastname: Predhomme
authors.forename: Amie
authors.initials: A
authors.lastname: Meditz
authors.forename: John
authors.initials: J
authors.lastname: Gerber
authors.forename: Courtney V
authors.initials: CV
authors.lastname: Fletcher
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000032:analysis*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives* / Q000032:analysis; D054306:Dideoxynucleotides; D004334:Drug Administration Schedule; D005260:Female; D018023:HIV Seronegativity / Q000502:physiology*; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000032:analysis; D013942:Thymine Nucleotides / Q000032:analysis*; D015215:Zidovudine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; C417268:lamivudine triphosphate; D019259:Lamivudine; D015215:Zidovudine; D003570:Cytidine Triphosphate; C052873:zidovudine triphosphate