In vitro interactions between apricitabine and other deoxycytidine analogues
In vitro interactions between apricitabine and other deoxycytidine analogues
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DOI：
10.1128/aac.01204-06
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发表时间：
2007-08-01
影响因子：
4.9
通讯作者：
Collins, P.
中科院分区：
文献类型：
--
作者：
Bethell, R.;De Muys, J.;Collins, P.
Apricitabine是一种新型脱氧胞苷类似物逆转录酶抑制剂，正在开发用于治疗人类免疫缺陷病毒1型（HIV-1）感染。阿普利他滨被脱氧胞苷激酶磷酸化为活性三磷酸，脱氧胞苷激酶也负责拉米夫定（M）和恩曲他滨（FrQ）的细胞内磷酸化;因此，进行体外研究以研究阿普利他滨与这些药物之间可能的相互作用。将人外周血单核细胞（PBMC）与不同浓度的3 H标记或未标记的阿曲他滨、3 TC或FM孵育24 h，通过高效液相色谱法测定母体化合物及其磷酸化衍生物的细胞内浓度。在其他实验中，在各种浓度的阿西他滨和3 TC存在下，在感染了携带M184 V的HIV-1的PBMC中测量病毒逆转录酶活性。[3 H]阿曲他滨和[3 H] 3 TC在细胞内代谢形成单磷酸、二磷酸和三磷酸。3 TC和FrC（1至10 μ M）引起阿曲他滨磷酸化的浓度依赖性降低;相反，高达30 μ M浓度的阿曲他滨对3 TC或FM的磷酸化没有影响。阿曲他滨和3 TC的组合降低了阿曲他滨抗HIV-1：在3 TC存在下，产生50%病毒逆转录酶抑制的阿西他滨浓度增加2 - 5倍。这些发现表明，具有相似作用模式的核苷类逆转录酶抑制剂可能显示出影响其抗病毒疗效的生化相互作用。因此，至关重要的是，新的和现有的代理商的组合之间的潜在相互作用进行彻底调查，这样的组合被引入临床实践之前。
Apricitabine is a novel deoxycytidine analogue reverse transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Apricitabine is phosphorylated to its active triphosphate by deoxycytidine kinase, which is also responsible for the intracellular phosphorylation of lamivudine (M) and emtricitabine (FrQ; hence, in vitro studies were performed to investigate possible interactions between apricitabine and these agents. Human peripheral blood mononuclear cells (PBMC) were incubated for 24 h with various concentrations of 3 H-labeled or unlabeled apricitabine, 3TC, or FM Intracellular concentrations of parent compounds and their phosphorylated derivatives were measured by highperformance liquid chromatography. In other experiments, viral reverse transcriptase activity was measured in PBMC infected with HIV-1 bearing M184V in the presence of various concentrations of apricitabine and 3TC. [3 H]apricitabine and [3 H]3TC were metabolized intracellularly to form mono-, di-, and triphosphates. 3TC and FrC (1 to 10 tLM) produced concentration-dependent decreases in apricitabine phosphorylation; in contrast, apricitabine at concentrations of up to 30 mu M had no effect on the phosphorylation of 3TC or FM The combination of apricitabine and 3TC reduced the antiviral activity of apricitabine against HIV-1: apricitabine concentrations producing 50% inhibition of viral reverse transcriptase were increased two- to fivefold in the presence of 3TC. These findings suggest that nucleoside reverse transcriptase inhibitors with similar modes of action may show biochemical interactions that affect their antiviral efficacy. It is therefore essential that potential interactions between combinations of new and existing agents be thoroughly investigated before such combinations are introduced into clinical practice.