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Alcohol induced changes in cellular pharmacokinetics and pharmacodynamics of elvitegravir and darunavir in HIV‐1 infected monocytic cells
Author(s) -
Midde Narasimha M,
Sinha Namita,
Gong Yuqing,
Meibohm Bernd,
Kumar Santosh
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.822.3
Subject(s) - elvitegravir , darunavir , cobicistat , pharmacology , chemistry , ethanol , pharmacokinetics , cyp3a4 , biology , viral load , cytochrome p450 , immunology , biochemistry , metabolism , human immunodeficiency virus (hiv) , antiretroviral therapy
Alcohol consumption is negatively associated with antiretroviral therapy (ART) adherence 1 . Maintenance of optimal ART levels in monocytes and/or macrophages, the known HIV viral reservoirs, is essential to suppress HIV viral replication. Previously, we reported ethanol mediated alterations in metabolism of elvitegravir (EVG) in human liver microsomes 2 . The objective of this study was to investigate whether the ethanol exposure alters the intracellular concentration of EVG in HIV‐infected monocytic cells. Methods HIV‐infected U937 (U1) cells were treated with EVG (5 μM), EVG+Cobicistat (COBI) (2 μM), EVG+ethanol (20 mM), and EVG+COBI+ethanol combinations and collected cells at different time intervals up to 24 hours. EVG concentration was measured using LC MS/MS. HIV p24 levels were assessed by ELISA and cytochrome P450 (CYP) 3A4, multidrug resistance‐associated protein 1 (MRP1), and multidrug resistance protein 1 (MDR1) levels by In‐Cell Western (ICW) technique. One way ANOVA and student t‐test were employed wherever appropriate and the p‐value ≤ 0.05 was considered significant. Results Ethanol treatment demonstrated a significant decrease of area under the concentration curve (AUC) and maximum concentration (C max ) values of EVG, and increased the HIV p24 levels despite the presence of ART. Moreover, exposure of MRP1 inhibitor along with EVG and COBI reduced ethanol influence on EVG concentration but did not affect the p24 levels. Finally, our ICW data suggest that ethanol induces the expression of CYP3A4, MRP1 and MDR1 proteins. Conclusions Overall, these findings suggest that ethanol reduces EVG intracellular availability in in vitro conditions, at least partially, by modifying CYP3A4, MRP1 and MDR1 protein levels. This evidence warrants further ex vivo investigation of the effects of alcohol on the availability of antiretroviral drugs at the cellular level. Support or Funding Information This research was supported by grant from the National Institute of Health to Santosh Kumar (NIAAA/NIH AA‐022063)