Division of Clinical Pharmacology and Toxicology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
J Antimicrob Chemother. 2011 Jul;66(7):1573-81. doi: 10.1093/jac/dkr151. Epub 2011 Apr 19.
The site of pharmacological activity of raltegravir is intracellular. Our aim was to determine the extent of raltegravir cellular penetration and whether raltegravir total plasma concentration (C(tot)) predicts cellular concentration (C(cell)).
Open-label, prospective, pharmacokinetic study on HIV-infected patients on a stable raltegravir-containing regimen. Plasma and peripheral blood mononuclear cells were simultaneously collected during a 12 h dosing interval after drug intake. C(tot) and C(cell) of raltegravir, darunavir, etravirine, maraviroc and ritonavir were measured by liquid chromatography coupled to tandem mass spectrometry after protein precipitation. Longitudinal mixed effects analysis was applied to the C(cell)/C(tot) ratio.
Ten HIV-infected patients were included. The geometric mean (GM) raltegravir total plasma maximum concentration (C(max)), minimum concentration (C(min)) and area under the time-concentration curve from 0-12 h (AUC(0-12)) were 1068 ng/mL, 51.1 ng/mL and 4171 ng·h/mL, respectively. GM raltegravir cellular C(max), C(min) and AUC(0-12) were 27.5 ng/mL, 2.9 ng/mL and 165 ng·h/mL, respectively. Raltegravir C(cell) corresponded to 5.3% of C(tot) measured simultaneously. Both concentrations fluctuate in parallel, with C(cell)/C(tot) ratios remaining fairly constant for each patient without a significant time-related trend over the dosing interval. The AUC(cell)/AUC(tot) GM ratios for raltegravir, darunavir and etravirine were 0.039, 0.14 and 1.55, respectively.
Raltegravir C(cell) correlated with C(tot) (r = 0.86). Raltegravir penetration into cells is low overall (∼5% of plasma levels), with distinct raltegravir cellular penetration varying by as much as 15-fold between patients. The importance of this finding in the context of development of resistance to integrase inhibitors needs to be further investigated.
拉替拉韦的药理活性部位在细胞内。本研究旨在确定拉替拉韦在细胞内的渗透程度，以及拉替拉韦的总血浆浓度（C(tot)）是否能预测细胞浓度（C(cell)）。
对接受稳定拉替拉韦方案治疗的 HIV 感染患者进行开放性、前瞻性药代动力学研究。在药物摄入后 12 小时的给药间隔期间，同时采集血浆和外周血单核细胞。通过蛋白沉淀后，采用液相色谱-串联质谱法测量拉替拉韦、达芦那韦、依曲韦林、马拉维若和利托那韦的 C(tot)和 C(cell)。采用纵向混合效应分析方法对 C(cell)/C(tot)比值进行分析。
纳入 10 例 HIV 感染患者。拉替拉韦总血浆最大浓度（C(max)）、最小浓度（C(min)）和 0-12 小时时浓度-时间曲线下面积（AUC(0-12)）的几何均数（GM）分别为 1068ng/mL、51.1ng/mL 和 4171ng·h/mL。拉替拉韦细胞 C(max)、C(min)和 AUC(0-12)的 GM 分别为 27.5ng/mL、2.9ng/mL 和 165ng·h/mL。拉替拉韦 C(cell)相当于同时测量的 C(tot)的 5.3%。两种浓度平行波动，C(cell)/C(tot)比值在整个给药间隔内对每个患者保持相对恒定，无明显的时间相关趋势。拉替拉韦、达芦那韦和依曲韦林的 AUC(cell)/AUC(tot) GM 比值分别为 0.039、0.14 和 1.55。
拉替拉韦的 C(cell)与 C(tot)相关（r=0.86）。拉替拉韦整体向细胞内渗透程度较低（约为血浆水平的 5%），不同患者的拉替拉韦细胞内渗透程度差异高达 15 倍。在整合酶抑制剂耐药的背景下，这一发现的重要性需要进一步研究。
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