PHARMACOKINETICS OF ZIDOVUDINE PHOSPHORYLATION IN PERIPHERAL-BLOOD MONONUCLEAR-CELLS FROM PATIENTS INFECTED WITH HUMAN-IMMUNODEFICIENCY-VIRUS

被引:66
作者
STRETCHER, BN
PESCE, AJ
FRAME, PT
STEIN, DS
机构
[1] UNIV CINCINNATI,COLL MED,DEPT PATHOL & LAB MED,CINCINNATI,OH 45267
[2] UNIV CINCINNATI,COLL MED,DEPT INTERNAL MED,CINCINNATI,OH 45267
[3] NIAID,DIV AIDS,BETHESDA,MD 20892
关键词
D O I
10.1128/AAC.38.7.1541
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
As part of an effort towards optimization of dosing of zidovudine (ZDV), formation and elimination of total phosphorylated ZDV (ZDVPt) in peripheral blood mononuclear cells were examined in 21 asymptomatic human immunodeficiency virus-infected patients during their first 24 weeks of therapy (AIDS Clinical Trials Group Protocol 161). Intracellular concentrations of ZDVPt were measured with a previously described and validated radioimmunoassay technique. Although ZDV phosphorylation occurred readily upon initiation of therapy, it declined with time; the area under the concentration-time curve (AUC) at week 4 (mean +/- standard deviation, 3.41 +/- 0.93 pmol.h/10(6) cells) was significantly greater than that at week 24 (2.19 +/- 1.10 pmol.h/10(6) cells). Plasma ZDV AUC did not change with time and did not correlate with ZDVPt AUC. In dose-response experiments (20 to 100 mg orally), phosphorylation did not proportionally increase with increasing plasma ZDV concentrations. Similarly, compared with a single dose, two doses of ZDV over an 8-h period resulted in little ZDVPt increase in cells relative to increases in plasma ZDV concentrations. The half-life of intracellular ZDVPt was twice that of plasma ZDV (4 versus 2 h), suggesting that an every-8-h dosing regimen is justifiable. These findings suggest that metabolism of ZDV to its active intracellular forms may be saturable in some patients, is poorly correlated with plasma concentrations, and diminishes over time. These findings have implications for future development and management of anti-human immunodeficiency virus nucleoside therapy.
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页码:1541 / 1547
页数:7
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