JAC Advance Access originally published online on June 20, 2008
Journal of Antimicrobial Chemotherapy 2008 62(4):738-745; doi:10.1093/jac/dkn247
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Original research |
Cytokine and sex hormone effects on zidovudine- and lamivudine-triphosphate concentrations in vitro
1 Department of Pharmaceutical Sciences, University of Colorado Denver, Denver, CO, USA 2 Department of Preventive Medicine and Biometrics, University of Colorado Denver, Denver, CO, USA
Received 15 April 2008; returned 20 May 2008; revised 22 May 2008; accepted 27 May 2008
* Correspondence address. Department of Pharmaceutical Sciences, University of Colorado Denver, Box C238, 4200 E. 9th Avenue, Denver, CO 80262, USA. Tel: +1-303-315-1720; Fax: +1-303-315-1721; E-mail: peter.anderson{at}uchsc.edu
Introduction: Elevated zidovudine- and lamivudine-triphosphates have been observed in peripheral blood mononuclear cells (PBMCs) from females versus males and in patients with high inflammatory states versus lower inflammatory states. Consistent with high triphosphate exposures, these same patient groups also experience elevated rates of toxicity, including lipoatrophy. The purpose of this study was to evaluate the effects of oestradiol, progesterone and testosterone as well as tumour necrosis factor (TNF)-
and interferon (IFN)- on zidovudine- and lamivudine-triphosphates in PBMCs and, for the cytokines, in 3T3-L1 adipocytes.
Methods: Multiple replicates of adipocytes and human PBMCs were incubated with experimental versus control conditions using several cytokine and sex hormone doses. Zidovudine- and lamivudine-triphosphate concentrations were determined with validated LC-MS-MS assays. A mixed effects, cell means model that accounted for experiment number was used to evaluate the effects of experimental conditions relative to control.
Results: In adipocytes, TNF- doses below 2 ng/mL increased zidovudine-triphosphate by 18% (5–31%). Lamivudine-triphosphate was not detectable in adipocytes. In PBMCs, pooled IFN- doses (0.1–10 U/mL) decreased zidovudine-triphosphate 26% (10–42%); 100 and 1000 ng/mL of progesterone decreased lamivudine-triphosphate by 22% (1–43%) and 47% (25–68%), respectively. Pooled testosterone doses (10–1000 ng/mL) decreased lamivudine-triphosphate by 24% (7–41%). No other statistically significant effects were observed.
Conclusions: We found evidence that sex hormones and cytokines influence zidovudine-triphosphate and lamivudine-triphosphate slightly in PBMCs and adipocytes in vitro. These findings provide insight and scientific direction to address inflammation-dependent and sex-dependent phosphorylation and responses in patients.
Keywords: nucleoside analogues , pharmacology , intracellular , toxicity , phosphorylation