Concentrations of zidovudine- and lamivudine-triphosphate according to cell type in HIV-seronegative adults

Peter L. Anderson, Jia Hua Zheng, Tracy King, Lane R. Bushman, Julie Predhomme, Amie Meditz, John Gerber, Courtney V. Fletcher

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Abstract

INTRODUCTION: 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 ≥ 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 × 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 × 10 cells (Friedman P = 0.01). In mixed model analyses: ZDV-TP (fmol/1 × 10 cells) = 42-0.32 (CD4%); P < 0.001 and 3TC-TP (pmol/1 × 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.

Original languageEnglish (US)
Pages (from-to)1849-1854
Number of pages6
JournalAIDS
Volume21
Issue number14
DOIs
StatePublished - Sep 1 2007

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HIV
Lamivudine
Blood Cells
T-Lymphocytes
Zidovudine
Volunteers
3'-azido-3'-deoxythymidine 5'-triphosphate
lamivudine triphosphate
triphosphoric acid
Liquid Chromatography
Mass Spectrometry

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Concentrations of zidovudine- and lamivudine-triphosphate according to cell type in HIV-seronegative adults. / Anderson, Peter L.; Zheng, Jia Hua; King, Tracy; Bushman, Lane R.; Predhomme, Julie; Meditz, Amie; Gerber, John; Fletcher, Courtney V.

In: AIDS, Vol. 21, No. 14, 01.09.2007, p. 1849-1854.

Research output: Contribution to journalArticle

Anderson, PL, Zheng, JH, King, T, Bushman, LR, Predhomme, J, Meditz, A, Gerber, J & Fletcher, CV 2007, 'Concentrations of zidovudine- and lamivudine-triphosphate according to cell type in HIV-seronegative adults', AIDS, vol. 21, no. 14, pp. 1849-1854. https://doi.org/10.1097/QAD.0b013e3282741feb
Anderson PL, Zheng JH, King T, Bushman LR, Predhomme J, Meditz A et al. Concentrations of zidovudine- and lamivudine-triphosphate according to cell type in HIV-seronegative adults. AIDS. 2007 Sep 1;21(14):1849-1854. https://doi.org/10.1097/QAD.0b013e3282741feb
Anderson, Peter L. ; Zheng, Jia Hua ; King, Tracy ; Bushman, Lane R. ; Predhomme, Julie ; Meditz, Amie ; Gerber, John ; Fletcher, Courtney V. / Concentrations of zidovudine- and lamivudine-triphosphate according to cell type in HIV-seronegative adults. In: AIDS. 2007 ; Vol. 21, No. 14. pp. 1849-1854.
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title = "Concentrations of zidovudine- and lamivudine-triphosphate according to cell type in HIV-seronegative adults",
abstract = "INTRODUCTION: 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 ≥ 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 × 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 × 10 cells (Friedman P = 0.01). In mixed model analyses: ZDV-TP (fmol/1 × 10 cells) = 42-0.32 (CD4{\%}); P < 0.001 and 3TC-TP (pmol/1 × 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.",
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T1 - Concentrations of zidovudine- and lamivudine-triphosphate according to cell type in HIV-seronegative adults

AU - Anderson, Peter L.

AU - Zheng, Jia Hua

AU - King, Tracy

AU - Bushman, Lane R.

AU - Predhomme, Julie

AU - Meditz, Amie

AU - Gerber, John

AU - Fletcher, Courtney V.

PY - 2007/9/1

Y1 - 2007/9/1

N2 - INTRODUCTION: 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 ≥ 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 × 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 × 10 cells (Friedman P = 0.01). In mixed model analyses: ZDV-TP (fmol/1 × 10 cells) = 42-0.32 (CD4%); P < 0.001 and 3TC-TP (pmol/1 × 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.

AB - INTRODUCTION: 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 ≥ 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 × 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 × 10 cells (Friedman P = 0.01). In mixed model analyses: ZDV-TP (fmol/1 × 10 cells) = 42-0.32 (CD4%); P < 0.001 and 3TC-TP (pmol/1 × 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.

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