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首页> 外文学位 >Intracellular drug -drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine.
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Intracellular drug -drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine.

机译：核苷类似物之间的细胞内药物相互作用会导致接受替诺福韦，拉米夫定和阿巴卡韦或二羟肌苷的三核苷组合的HIV患者出现早期病毒学衰竭。

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摘要

High level of virologic failure was observed in HIV patients receiving combinations of tenofovir (TFV), lamivudine (3TC) combined with either abacavir (ABC) or didanosine (ddI). To investigate the pharmacologic mechanisms involve with the virologic failures, a comprehensive study was undertaken to evaluate the intracellular concentration of the active moiety (ddNTP) of these respective nucleoside analogs.;Triple nucleoside combinations were tested at physiological concentrations revealed reductions of 5 to 33% of the respective ddNTP. In vitro studies evaluating TFV and ABC in a concentration dependent manner showed a reduction of 40% and 30% in intracellular CBV-TP and TFV-DP. Similar findings were demonstrated with TFV and ddI, where 40% and 25% reduction in ddATP and TFV-DP, respectively, was detected. The level of dATP and dGTP, endogenous nucleotides, were increased by 2.4- and 2.7-fold, respectively, when cells were treated with 20 muM TFV, which can dilute the effect of ddNTP.;The expression of MRP2 and MRP4 were increased in cells serially passaged in either ABC or TFV, which correlated with cellular viability in the presence of high concentrations of nucleosides. Moreover, these cells had significantly lower level of ddNTP accumulation as compared to the wild type counterparts.;A clinical study was undertaken to evaluate whether the in vitro findings were also observed in humans. The combination of ABC and TDF resulted in a 2-fold increase in intracellular TFV-DP in patients receiving the combination of ABC and TFV as compared to TDF alone. Increases in TFV-DP may be attributed to higher plasma level of TFV, which was detected in the second phase of this study. A 4-fold increase in CBV-TP was detected three of nine patients, while the other six (6/9) had a 41% reduction. The degree of CBV-TP reduction is consistent with what is seen in vitro.;These findings suggest that cellular adaptive are critical in reducing intracellular levels of nucleoside analogs and their corresponding ddNTP, which may increase risk of virologic failures. The underlying pharmacological mechanisms may include but are not limited to, the competitive inhibition of anabolic enzymes, increase expression of efflux transporters and increase dATP and dGTP, where the resultant effect is reduced antiviral activity.
机译：在接受替诺福韦（TFV），拉米夫定（3TC）联合阿巴卡韦（ABC）或去羟肌苷（ddI）组合的HIV患者中观察到高水平的病毒学衰竭。为了研究与病毒学失败有关的药理机制，进行了全面的研究以评估这些相应核苷类似物的活性部分（ddNTP）的细胞内浓度。;在生理浓度下测试了三种核苷组合，发现减少了5％至33％各自的ddNTP。以浓度依赖的方式评估TFV和ABC的体外研究表明，细胞内CBV-TP和TFV-DP降低了40％和30％。 TFV和ddI证实了类似的发现，其中ddATP和TFV-DP分别降低了40％和25％。当用20μMTFV处理细胞时，dATP和dGTP的内源性核苷酸水平分别增加了2.4倍和2.7倍，这可以稀释ddNTP的作用。细胞中MRP2和MRP4的表达增加。在ABC或TFV中连续传代，这与存在高浓度核苷时的细胞活力相关。此外，与野生型对应物相比，这些细胞的ddNTP积累水平明显更低。;进行了一项临床研究，以评估是否在人中也观察到了体外发现。与单独使用TDF相比，ABC和TDF的组合导致接受ABC和TFV组合的患者的细胞内TFV-DP增加了2倍。 TFV-DP的升高可能归因于TFV的血浆水平升高，这是在本研究的第二阶段中检测到的。在9例患者中，有3例CBV-TP升高了4倍，而其他6例（6/9）降低了41％。 CBV-TP降低的程度与体外观察到的一致。这些发现表明，细胞适应性对于降低核苷类似物及其相应的ddNTP的细胞内水平至关重要，这可能会增加病毒学失败的风险。潜在的药理机制可能包括但不限于同化酶的竞争性抑制，外排转运蛋白表达的增加以及dATP和dGTP的增加，其结果是抗病毒活性降低。

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  • 作者

    Bi, Lucun.;

  • 作者单位

    University of Southern California.;

  • 授予单位 University of Southern California.;
  • 学科 Pharmacology.;Pharmacy sciences.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 202 p.
  • 总页数 202
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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