title: 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.
authors.affiliation: Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis TN, United States of America.
authors.forename: Narasimha M
authors.initials: NM
authors.lastname: Midde
authors.affiliation: Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis TN, United States of America.
authors.forename: Namita
authors.initials: N
authors.lastname: Sinha
authors.affiliation: Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis TN, United States of America.
authors.forename: Pradeep B
authors.initials: PB
authors.lastname: Lukka
authors.affiliation: Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis TN, United States of America.
authors.forename: Bernd
authors.initials: B
authors.lastname: Meibohm
authors.affiliation: Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis TN, United States of America.
authors.forename: Santosh
authors.identifier: http://orcid.org/0000-0001-7846-5674
authors.initials: S
authors.lastname: Kumar
mesh_terms: D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000821:virology; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D015363:Quinolones; D000431:Ethanol; C509700:elvitegravir