Barry M G, Khoo S H, Veal G J, Hoggard P G, Gibbons S E, Wilkins E G, Williams O, Breckenridge A M, Back D J
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
AIDS. 1996 Oct;10(12):1361-7. doi: 10.1097/00002030-199610000-00008.
Zidovudine (ZDV) requires intracellular phosphorylation to ZDV triphosphate (ZDV-TP) prior to the inhibition of HIV replication. The effect of ZDV dose on the formation of intracellular phosphorylated metabolites may help define the optimum daily dose of ZDV, which is still unknown.
The plasma and intracellular phosphorylated metabolite concentrations of ZDV were determined over a 12 h period following oral administration of 100 and 300 mg ZDV to 10 HIV-seropositive patients at steady state during two dosing regimens (i.e., 100 mg three times daily and 300 mg twice daily). The intracellular ZDV phosphates, ZDV monophosphate (ZDV-MP), ZDV diphosphate (ZDV-DP) and ZDV-TP were measured in peripheral blood mononuclear cells using a combination of high-performance liquid chromatography and radioimmunoassay.
There was a greater than threefold increase in maximum plasma concentration (Cmax) following 300 mg ZDV when compared with 100 mg ZDV (mean +/- SD, 2.59 +/- 0.52 versus 0.70 +/- 0.14 mumol/l). The area under the concentration time curve (AUC0-12 h) was also significantly increased (4.59 +/- 0.79 versus 1.42 +/- 0.51 mumol/l x h) following 300 mg ZDV dose. For total intracellular ZDV phosphate metabolites the AUC0-12 h was doubled (7.64 +/- 3.67 versus 3.71 +/- 1.83 pmol/10(6) cells x h) in patients taking 300 mg ZDV compared with 100 mg. The AUC0-12 h for ZDV-MP was significantly increased at the higher dose (6.47 +/- 3.14 versus 2.77 +/- 1.70 pmol/10(6) cells x h), whereas the active moiety ZDV-TP was variable and not significantly different (0.42 +/- 0.42 versus 0.61 +/- 0.81 pmol/10(6) cells x h) following 100 and 300 mg ZDV.
Administration of 100 mg ZDV orally produces significantly less of the potentially toxic metabolite, ZDV-MP, and comparative, although variable, concentrations of the active metabolite ZDV-TP when compared with 300 mg ZDV orally. This finding supports clinical data indicating the efficacy of low-dose (300 mg daily) ZDV. The measurement of intracellular phosphorylated metabolites advances our understanding of the clinical pharmacology of ZDV.
齐多夫定（ZDV）在抑制HIV复制之前需要在细胞内磷酸化为三磷酸齐多夫定（ZDV-TP）。ZDV剂量对细胞内磷酸化代谢产物形成的影响可能有助于确定ZDV的最佳日剂量，目前该剂量仍不清楚。
在两种给药方案（即每日3次，每次100mg和每日2次，每次300mg）的稳态期，对10例HIV血清阳性患者口服100mg和300mg ZDV后12小时内的血浆和细胞内磷酸化代谢产物浓度进行测定。使用高效液相色谱和放射免疫分析法相结合的方法，在外周血单核细胞中测量细胞内的齐多夫定磷酸盐，即齐多夫定一磷酸（ZDV-MP）、齐多夫定二磷酸（ZDV-DP）和ZDV-TP。
与100mg ZDV相比，300mg ZDV后的最大血浆浓度（Cmax）增加了三倍以上（平均值±标准差，2.59±0.52对0.70±0.14μmol/L）。300mg ZDV剂量后的浓度-时间曲线下面积（AUC0-12h）也显著增加（4.59±0.
