Alterations in cellular pharmacokinetics and pharmacodynamics of elvitegravir in response to ethanol exposure in HIV-1 infected monocytic (U1) cells.
Alterations in cellular pharmacokinetics and pharmacodynamics of elvitegravir in response to ethanol exposure in HIV-1 infected monocytic (U1) cells.
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DOI：
10.1371/journal.pone.0172628
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Kumar S
中科院分区：
文献类型：
--
作者：
Midde NM;Sinha N;Lukka PB;Meibohm B;Kumar S
酒精消费量与抗逆转录病毒治疗（ART）的依从性和总体健康状况呈负相关。先前，我们证明了乙醇介导的人肝微粒体中埃替拉韦（EVG）代谢的改变。在目前的研究中，我们研究了乙醇对EVG在HIV感染的单核细胞（U1）中的药代动力学和药效学相互作用的影响。用5 μM EVG、2 μM Cobicistat（COBI）（一种加强药物）和20 mM乙醇处理U1细胞长达24小时。检测EVG、HIV p24水平、细胞色素P450（P450）3A4、MRP 1和MDR 1蛋白表达的变化。乙醇的存在对EVG和EVG联合COBI的总暴露量有显著影响。尽管存在药物，乙醇也增加了HIV复制，并且在MRP1和MDR1抑制剂存在下，这种升高的HIV复制降低。因此，在存在MRP 1抑制剂的情况下观察到EVG浓度略微增加，但在存在MDR 1抑制剂的情况下未观察到。此外，与未处理组相比，在包括乙醇的处理组中显著诱导了CYP3A4、MRP 1和MDR 1蛋白水平。总之，这些发现表明，乙醇通过改变药物代谢和转运蛋白表达减少细胞内EVG暴露。本研究为进一步研究乙醇对EVG细胞内浓度的影响提供了有价值的证据。
Ethanol consumption is negatively associated with antiretroviral therapy (ART) adherence and general health in HIV positive individuals. Previously, we demonstrated ethanol-mediated alterations to metabolism of elvitegravir (EVG) in human liver microsomes. In the current study, we investigated ethanol influence on the pharmacokinetic and pharmacodynamic interactions of EVG in HIV infected monocytic (U1) cells. U1 cells were treated with 5 μM EVG, 2 μM Cobicistat (COBI), a booster drug, and 20 mM ethanol for up to 24 hours. EVG, HIV p24 levels, alterations in cytochrome P450 (CYP) 3A4, MRP1, and MDR1 protein expressions were measured. Presence of ethanol demonstrated a significant effect on the total exposures of both EVG and EVG in combination with COBI. Ethanol also increased the HIV replication despite the presence of drugs and this elevated HIV replication was reduced in the presence of MRP1 and MDR1 inhibitors. Consequently, a slight increase in EVG concentration was observed in the presence of MRP1 inhibitor but not with MDR1 inhibitor. Furthermore, CYP3A4, MRP1 and MDR1 protein levels were significantly induced in treatment groups which included ethanol compared to those with no treatment. In summary, these findings suggest that Ethanol reduces intra cellular EVG exposure by modifying drug metabolism and transporter protein expression. This study provides valuable evidence for further investigation of ethanol effects on the intracellular concentration of EVG in ex vivo or in vivo studies.
DOI：
10.1177/2325957413495567
发表时间：
2013-11
影响因子：
--
作者：
Gruber VA;Rainey PM;Lum PJ;Beatty GW;Aweeka FT;McCance-Katz EF
通讯作者：
McCance-Katz EF