Alterations in cellular pharmacokinetics and pharmacodynamics of elvitegravir in response to ethanol exposure in HIV-1 infected monocytic (U1) cells

Abstract

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.

The role of cytochrome P450 2E1 on ethanol-mediated oxidative stress and HIV replication in human monocyte-derived macrophages

“…Studies with HIV-1-infected macaques have shown increased viral load in the blood and cerebral compartments of chronic-drinking animals [8] . Moreover, previous reports from our lab suggest that ethanol reduced intracellular concentrations of antiretroviral drugs (elvitegravir, darunavir) in the HIV-1-infected U1 cell line [9] , [10] . Ethanol also increased HIV-1 replication despite the presence of elvitegravir [10] .…”

“…Moreover, previous reports from our lab suggest that ethanol reduced intracellular concentrations of antiretroviral drugs (elvitegravir, darunavir) in the HIV-1-infected U1 cell line [9] , [10] . Ethanol also increased HIV-1 replication despite the presence of elvitegravir [10] . Despite this, little is currently known about the cellular pathways involved with alcohol consumption and HIV-1 replication.…”

Influence of Ethanol on Darunavir Hepatic Clearance and Intracellular PK/PD in HIV-Infected Monocytes, and CYP3A4-Darunavir Interactions Using Inhibition and in Silico Binding Studies

“…Additionally, we recently reported that ethanol exposure decreases the intracellular EVG AUC tot and C max values in the absence of pharmacoenhancer, cobicistat in monocytes (20). Clinically relevant concentration of ethanol (20 mM) exposure to U1 cells resulted in a 11% decrease in AUC tot of DRV compared to DRV alone (t(4) = 4.6, p = 0.0102, student t test, Fig.…”

Choosing the right pharmacotherapeutic strategy for HIV maintenance in patients with alcohol addiction

“…Further, another commonly used ARV, elvitegravir (EVG), is metabolized by CYP3A4 and a strong CYP3A4 inhibitor such as cobicistat (COBI) is coadministered as a booster to increase EVG bioavailability. Recently, Kumar group showed that the ethanol exposure decreases the intracellular levels of EVG alone and also in combination with COBI in HIV-infected macrophages [19,20]. Subsequently, co-exposing cells to EVG or EVG + COBI along with ethanol showed increased viral replication by 31% and 19%, respectively, relative to control groups that did not receive ethanol [19].…”

“…Recently, Kumar group showed that the ethanol exposure decreases the intracellular levels of EVG alone and also in combination with COBI in HIV-infected macrophages [19,20]. Subsequently, co-exposing cells to EVG or EVG + COBI along with ethanol showed increased viral replication by 31% and 19%, respectively, relative to control groups that did not receive ethanol [19]. Therefore, EVG level should be monitored in HIV patients who consume alcohol to attain sustained virological suppression.…”