K Peter1, J G Gambertoglio. 1. Department of Clinical Pharmacy, University of California, San Francisco 94143-0622, USA.
Abstract
BACKGROUND: Resistance of human immunodeficiency virus (HIV) to zidovudine (AZT) has been associated with mutations in the viral reverse transcriptase gene. However, recent studies suggest that host cellular factors such as a decreased thymidine kinase activity or an increased cellular P-glycoprotein expression may be important. This study compared concentrations of zidovudine monophosphate, zidovudine diphosphate, and zidovudine triphosphate with P-glycoprotein expression in peripheral blood mononuclear cells from patients receiving long-term (> 18 months) and short-term (< 2 months) zidovudine treatment. METHODS: Ten subjects in the short-term group and 11 subjects in the long-term group with CD4 counts between 300 and 500 received a single oral dose of zidovudine (200 mg) after a 24-hour washout period. Blood samples were collected at 0, 1, 2, 4, and 6 hours. Intracellular nucleotide concentrations were measured by a combined HPLC-radioimmunoassay method, and P-glycoprotein expression was determined by fluorescence activated cell sorting (FACS) analysis with use of the monoclonal mouse antibody MRK-16. RESULTS: Zidovudine monophosphate was the predominant compound, accounting for 73.4% +/- 7.1% (SD) of the total phosphates in the long-term treatment group and 74.2% +/- 15.0% (SD) in the short-term group. Zidovudine diphosphate accounted for 13.3% +/- 3.3% (SD) in the long-term group and 12.5% +/- 6.6% (SD) in the short-term group. Zidovudine triphosphate accounted for 13.4% +/- 4.1% (SD) in the long-term group and 13.5% +/- 8.3% (SD) in the short-term group. Mean peak concentrations for the active zidovudine triphosphate were 0.04 +/- 0.02 (SD) pmol/10(6) cells in both groups. Comparison of the individual zidovudine phosphate concentrations and P-glycoprotein expression revealed no significant difference in the two patient populations. CONCLUSIONS: These data suggest that intracellular phosphorylation does not change over time and that zidovudine does not select for P-glycoprotein expressing cells.
BACKGROUND: Resistance of human immunodeficiency virus (HIV) to zidovudine (AZT) has been associated with mutations in the viral reverse transcriptase gene. However, recent studies suggest that host cellular factors such as a decreased thymidine kinase activity or an increased cellular P-glycoprotein expression may be important. This study compared concentrations of zidovudine monophosphate, zidovudine diphosphate, and zidovudine triphosphate with P-glycoprotein expression in peripheral blood mononuclear cells from patients receiving long-term (> 18 months) and short-term (< 2 months) zidovudine treatment. METHODS: Ten subjects in the short-term group and 11 subjects in the long-term group with CD4 counts between 300 and 500 received a single oral dose of zidovudine (200 mg) after a 24-hour washout period. Blood samples were collected at 0, 1, 2, 4, and 6 hours. Intracellular nucleotide concentrations were measured by a combined HPLC-radioimmunoassay method, and P-glycoprotein expression was determined by fluorescence activated cell sorting (FACS) analysis with use of the monoclonal mouse antibody MRK-16. RESULTS:Zidovudine monophosphate was the predominant compound, accounting for 73.4% +/- 7.1% (SD) of the total phosphates in the long-term treatment group and 74.2% +/- 15.0% (SD) in the short-term group. Zidovudine diphosphate accounted for 13.3% +/- 3.3% (SD) in the long-term group and 12.5% +/- 6.6% (SD) in the short-term group. Zidovudine triphosphate accounted for 13.4% +/- 4.1% (SD) in the long-term group and 13.5% +/- 8.3% (SD) in the short-term group. Mean peak concentrations for the active zidovudine triphosphate were 0.04 +/- 0.02 (SD) pmol/10(6) cells in both groups. Comparison of the individual zidovudine phosphate concentrations and P-glycoprotein expression revealed no significant difference in the two patient populations. CONCLUSIONS: These data suggest that intracellular phosphorylation does not change over time and that zidovudine does not select for P-glycoprotein expressing cells.
Authors: Y Wattanagoon; K Na Bangchang; P G Hoggard; S H Khoo; S E Gibbons; D Phiboonbhanakit; J Karbwang; D J Back Journal: Antimicrob Agents Chemother Date: 2000-07 Impact factor: 5.191
Authors: P G Hoggard; J Lloyd; S H Khoo; M G Barry; L Dann; S E Gibbons; E G Wilkins; C Loveday; D J Back Journal: Antimicrob Agents Chemother Date: 2001-03 Impact factor: 5.191