Intracellular and plasma pharmacokinetics of efavirenz in HIV-infected individuals
Intracellular and plasma pharmacokinetics of efavirenz in HIV-infected individuals
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DOI：
10.1093/jac/dki308
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发表时间：
2005-10-01
影响因子：
5.2
通讯作者：
Back, DJ
中科院分区：
文献类型：
--
作者：
Almond, LM;Hoggard, PG;Back, DJ
目的：依非韦伦的作用部位位于 HIV 感染的细胞内。因此，测量依非韦伦的细胞内 (IC) 浓度可以进一步了解治疗失败的情况，特别是在尽管血浆水平充足且缺乏可检测的病毒耐药性的情况下仍发生病毒学反弹的情况。在此，我们确定了依非韦伦的 IC 和血浆药代动力学及其与血浆蛋白结合和 P-糖蛋白（P-gp，一种活性药物外排转运蛋白）表达的关系。 患者和方法：在 24 小时内收集 10 名接受依非韦伦（600 mg 每天一次加两种核苷逆转录酶抑制剂）治疗的 HIV 感染患者的静脉血样本 给药间隔。分离血浆和外周血单核细胞（PBMC）。使用超滤分离血浆蛋白结合和未结合的依非韦伦。使用 HPLC-UV 定量 IC（或细胞相关）、总血浆和未结合血浆依非韦伦水平。通过流式细胞术测量P-gp表达。然后使用非房室分析计算浓度-时间曲线下面积 (AUC(0-24))，并将 IC 累积量表示为 IC 与血浆 AUC(0-24) 的比率。结果：中位（范围）％未结合和 IC 累积比率分别为 0.6% (0.4-1.5%) 和 1.3 (0.7-3.3)。 IC 与总 AUC(0-24) 之间存在线性关系（r(2) = 0.59，P = 0.01），但未结合的 AUC(0-24) 之间不存在线性关系（r(2) = 0.13，P = 0.75）。观察到 IC AUC(0-24) 和未结合百分比之间呈负相关 (r(2) = 41，P = 0.05）。 IC AUC(0-24) 和细胞表面 P-gp 表达之间没有关系（r(2) < 0.01，P = 0.98）。结论：血浆中依非韦伦结合百分比与 IC 积累之间存在直接关系，这意味着依非韦伦的 IC 积累与 IC 蛋白或其他细胞成分的结合有关。现在需要研究细胞内未结合的抗逆转录病毒药物的浓度。
Objectives: The site of action of efavirenz is inside HIV-infected cells. Measurement of intracellular (IC) concentrations of efavirenz may therefore provide further understanding of therapeutic failure, especially where virological rebound occurs despite adequate plasma levels, and a lack of detectable viral resistance. Here, we determined IC and plasma pharmacokinetics of efavirenz and their relationship with plasma protein binding and P-glycoprotein (P-gp, an active drug efflux transporter) expression.Patients and methods: Venous blood samples from 10 HIV-infected patients receiving efavirenz (600 mg once a day plus two nucleoside reverse transcriptase inhibitors) were collected over the 24 h dosing interval. Plasma and peripheral blood mononuclear cells (PBMCs) were isolated. Plasma protein bound and unbound efavirenz were separated using ultrafiltration. IC (or cell-associated), total plasma and unbound plasma efavirenz levels were quantified using HPLC-UV. P-gp expression was measured by flow cytometry. Area under the concentration-time curves (AUC(0-24)) were then calculated using non-compartmental analyses and the IC accumulation expressed as a ratio of IC to plasma AUC(0-24).Results: The median (range) % unbound and IC accumulation ratio was 0.6% (0.4-1.5%) and 1.3 (0.7-3.3), respectively. There was a linear relationship between IC and total AUC(0-24) (r(2) = 0.59, P = 0.01) but not unbound AUC(0-24) (r(2) = 0.13, P = 0.75). An inverse correlation between IC AUC(0-24) and % unbound was observed (r(2) = 41, P = 0.05). There was no relationship between IC AUC(0-24) and P-gp expression on the cell surface (r(2) < 0.01, P = 0.98).Conclusions: There was a direct relationship between % bound efavirenz in plasma and IC accumulation implying that the IC accumulation of efavirenz is related to binding to IC proteins or other cellular constituents. Studies investigating the unbound concentration of antiretrovirals inside the cell are now required.