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

Narasimha M Midde,Namita Sinha,Pradeep B Lukka,Bernd Meibohm,Santosh Kumar,Fatah Kashanchi

doi:10.1371/journal.pone.0172628

Narasimha M Midde, Namita Sinha + Show 4 more

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https://doi.org/10.1371/journal.pone.0172628

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Journal: PloS one	Publication Date: Feb 23, 2017
Citations: 16	License type: CC BY 4.0

Affiliation: University of Tennessee Health Science Center

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.

Highlights

Active antiretroviral therapy (HAART) regimen consisting of integrase strand transfer inhibitors (INSTI), nucleoside reverse transcriptase inhibitors (NRTI), nonnucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI) dramatically transformed HIV infection from fatal to a chronic but manageable disease
The mean intracellular concentration-time curve for EVG, EVG co-exposed with COBI or ethanol, and EVG co-exposed with both COBI and ethanol are shown in Fig 1 and Table 1
It is conceived that small molecules that interact with ethanol dehydrogenase or CYP2E1 and are likely to be influenced by ethanol exposure

Summary

Introduction

Active antiretroviral therapy (HAART) regimen consisting of integrase strand transfer inhibitors (INSTI), nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTI), nonnucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI) dramatically transformed HIV infection from fatal to a chronic but manageable disease. Among different classes of drugs, INSTIs such as elvitegravir (EVG), dolutegravir or raltegravir have become ‘standard’ drugs in the recommended regimens owing their superior efficacy and safety in clinical trials and retrospective evaluations[1, 2]. Owing to most HAART therapeutic intracellular targets, it is of utmost importance to understand the intracellular pharmacokinetics of these essential drugs. This was further substantiated by several clinical studies which demonstrated a weak or no correlation of plasma INSTI, NRTIs or PIs concentration with antiviral efficacy in the treatment of HIV infected patients[5,6,7,8]

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