Intracellular Concentration of Protease Inhibitors in HIV-1--Infected Patients: Correlation with MDR-1 Gene Expression and Low Dose of Ritonavir
Intracellular Concentration of Protease Inhibitors in HIV-1--Infected Patients: Correlation with MDR-1 Gene Expression and Low Dose of Ritonavir
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HIV-1 感染患者的细胞内蛋白酶抑制剂浓度：与 MDR-1 基因表达和低剂量利托那韦的相关性
作者：
S. Chaillou;J. Durant;R. Garraffo;E. Georgenthum;C. Roptin;P. Clevenbergh;Brigitte Dunais;V. Mondain;P. Roger;P. Dellamonica
摘要背景：蛋白酶抑制剂（PI）是多药耐药基因（MDR-1）编码的P-糖蛋白（P-gp/170）的底物。HIV感染与P-gp表达增加有关。MDR基因过表达在临床药代动力学中的作用尚不清楚。方法：我们通过HPLC测定了血浆（P）和外周血单核细胞（PBMC）中PI的谷值和峰值浓度。（细胞内浓度[IC]）来自49名接受不同治疗组合的HIV感染患者：奈非那韦（[NFV] n = 12）;茚地那韦（[IDV] n = 10）;安普那韦利托那韦100 bid/IDV 800 mg bid（n = 6）;利托那韦400 bid/IDV 400 mg bid（n = 3）;利托那韦100 bid/沙奎那韦600 mg tid（n = 9）; APV 600 bid/RTV 100 mg bid（n = 4）。我们确定了每个治疗组的细胞内/血浆PI浓度的平均比值。采用半定量逆转录聚合酶链反应（RT-PCR）检测MDR-1基因表达。同时测定HIV病毒载量。结果：49例患者（平均年龄41 ± 8.7岁;平均CD 4细胞计数418 [57-972];平均HIV RNA 2.1 ± 0.8 log 10）入组研究。过表达MDR-1基因的患者具有显著较低的细胞内PI谷水平（p = 0.02）或较低的细胞内PI积累（p = 0.042）。在可检测到RTV细胞内浓度的联合方案中，接受低剂量RTV治疗的患者显示缺乏MDR-1基因表达（p = .01）。HIV RNA < 40拷贝/mL的患者有显著更高的RTV细胞内蓄积（p = 0.029）。结论：HIV感染者PI的IC与MDR-1基因的过度表达呈负相关。检测不到的病毒载量与使用低剂量RTV相关，可能与药物更好的细胞内蓄积有关。然而，需要进一步的调查来证实这些结果。
Abstract Background: Protease inhibitors (PIs) are substrates for the P-glycoprotein (P-gp/170) encoded by the multi-drug resistance gene (MDR-1). HIV infection is associated with increased expression of P-gp. The role of MDR gene overexpression in clinical pharmacokinetics is not known. Method: We determined by HPLC, at trough and peak levels, the current PI concentrations in plasma (P) and in peripheral blood mononuclear cells (PBMCs) (intracellular concentration [IC]) from 49 HIV-infected patients receiving different treatment combinations: nelfinavir ([NFV] n = 12); indinavir ([IDV] n = 10); amprenavir ([APV] n = 5); ritonavir (RTV) 100 bid/IDV 800 mg bid (n = 6); RTV 400 bid/IDV 400 mg bid (n = 3); RTV 100 bid/saquinavir (SQV) 600 mg tid (n = 9); APV 600 bid/RTV 100 mg bid (n = 4). We determined the mean ratio of intracellular/plasma PI concentration for each treatment group. The MDR-1 gene expression was determined by a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). HIV viral load was simultaneously measured. Results: 49 patients (mean age 41 ± 8.7 years; mean CD4 cell count 418 [57-972]; mean HIV RNA 2.1 ± 0.8 log10) were included in the study. Patients who overexpressed the MDR-1 gene had significantly lower trough intracellular PI levels (p = .02) or lower intracellular accumulation of PI (p = .042). Patients treated with low-dose RTV in combined regimens with detectable RTV intracellular concentration showed lack of MDR-1 gene expression (p = .01). Patients with HIV RNA < 40 copies/mL had significantly higher RTV intracellular accumulation (p = .029). Conclusion: In HIV-infected patients, IC of PI is inversely correlated with MDR-1 gene overexpression. Undetectable viral load was associated with the use of low-dose RTV, probably linked to better intracellular accumulation of the drug. Nevertheless, further investigation is needed to confirm these results.
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DOI：
--
发表时间：
2000-06
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
E. Choo;B. Leake;C. Wandel;H. Imamura;A. J. Wood;G. Wilkinson;R. Kim
通讯作者：
E. Choo;B. Leake;C. Wandel;H. Imamura;A. J. Wood;G. Wilkinson;R. Kim
影响因子：
20.3
作者：
D. Drach;Shourong Zhao;J. Drach;R. Mahadevia;Claus Gattringer;Heinz Huber;M. Andreeff
通讯作者：
D. Drach;Shourong Zhao;J. Drach;R. Mahadevia;Claus Gattringer;Heinz Huber;M. Andreeff
人类免疫缺陷病毒 I 诱导的 P-糖蛋白表达。
DOI：
10.1016/0006-291x(90)90783-j
发表时间：
1990
影响因子：
3.1
作者：
Gollapudi,S;Gupta,S
通讯作者：
Gupta,S
HIV 蛋白酶抑制剂与 ATP 依赖性药物输出蛋白的相互作用。
影响因子：
3.6
作者：
Gutmann,H;Fricker,G;Drewe,J;Toeroek,M;Miller,DS
通讯作者：
Miller,DS
影响因子：
15.9
作者：
Kim, RB;Fromm, MF;Wilkinson, GR
通讯作者：
Wilkinson, GR