Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus-infected individuals
Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus-infected individuals
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DOI：
10.1016/j.clpt.2005.04.004
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发表时间：
2005-08-01
影响因子：
6.7
通讯作者：
Khoo, SH
中科院分区：
文献类型：
--
作者：
Almond, LM;Edirisinghe, D;Khoo, SH
背景和目的：奈韦拉平的血浆浓度与人类免疫缺陷病毒（HIV）治疗结果相关。然而，由于奈韦拉平的作用部位在HIV感染细胞内，细胞内浓度可能更好地与抗病毒药物暴露相关。研究改变奈韦拉平细胞内药代动力学的因素也有助于我们理解治疗失败。我们的目的是确定细胞内（或细胞相关）奈韦拉平浓度在整个给药间隔和相关蛋白结合和P-糖蛋白（P-gp）表达的细胞内exposure.Methods：血浆和外周血单核细胞分离的血液样本从10个HIV感染患者在0，2，4，8，和12小时后给药。通过液相色谱-串联质谱法测定细胞内和血浆（总和未结合）浓度，并计算细胞内与总血浆暴露量的比值（浓度-时间曲线下面积）。结果：中位细胞内蓄积比为0.005（范围0.001-0.054），在给药间隔内保持不变。奈韦拉平较高的血浆浓度和较低的细胞浓度之间存在相关性（总r（2）= 0.62，P = 0.007）。未结合奈韦拉平百分比与细胞内奈韦拉平之间无相关性。较高的血浆奈韦拉平暴露与较高的P-gp表达之间存在相关性（r（2）= 0.77，P = 0.03），而细胞内奈韦拉平暴露随着较高的P-gp表达而降低（r（2）= 0.62，P = 0.01）。结论：奈韦拉平的细胞内蓄积较低，在给药间隔期间未发生变化，与蛋白结合无关。在这项小型研究中，具有较高P-gp表达的细胞具有较低的奈韦拉平细胞浓度。需要进一步的研究来探索这种药物的流入和流出转运蛋白。
Background and Objective: Plasma concentrations of nevirapine have been linked to human immunodeficiency virus (HIV) treatment outcome. However, because the site of action of nevirapine is within HIV-infected cells, intracellular concentrations may better relate to antiviral exposure. Investigation of factors that alter the intracellular pharmacokinetics of nevirapine may also aid in our understanding of therapeutic failure. Our objective was to determine intracellular (or cell-associated) nevirapine concentrations over the full dosing interval and to relate protein binding and P-glycoprotein (P-gp) expression to intracellular exposure.Methods: Plasma and peripheral blood mononuclear cells were isolated from blood samples taken from 10 HIV-infected patients at 0, 2, 4, 8, and 12 hours after dosing. Intracellular and plasma (total and unbound) concentrations were determined by liquid chromatography-tandem mass spectrometry, and the ratios of intracellular to total plasma exposure (area under the concentration-time curves) were calculated. P-gp expression was measured by flow cytometry.Results: The median intracellular accumulation ratio was 0.005 (range, 0.001-0.054) and remained unchanged over the dosing interval. There was an association between higher plasma concentrations and lower cellular concentrations of nevirapine (total r(2) = 0.62, P = .007). There was no relationship between percent unbound nevirapine and intracellular nevirapine. There was a correlation between higher plasma nevirapine exposure and higher P-gp expression (r(2) = 0.77, P =.03), whereas intracellular nevirapine exposure decreased with higher P-gp expression (r(2) = 0.62, P = .01).Conclusions: The intracellular accumulation of nevirapine was low, did not change over the dosing interval, and was not related to protein binding. In this small study, cells with higher P-gp expression had lower cellular concentrations of nevirapine. Further studies are required to explore the influx and efflux transporter profile of this drug.