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Pharmaceutical Research

, Volume 34, Issue 9, pp 1925–1933 | Cite as

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

  • Narasimha M. MiddeEmail author
  • Yuqing Gong
  • Theodore J. Cory
  • Junhao Li
  • Bernd Meibohm
  • Weihua Li
  • Santosh KumarEmail author
Research Paper

Abstract

Purpose

Although the prevalence of alcohol consumption is higher in HIV+ people than general public, limited information is available on how alcohol affects the metabolism and bioavailability of darunavir (DRV).

Methods

DRV was quantified by using LC-MS/MS method. All in vitro experiments were performed using human liver microsomes and HIV-infected monocytic cells. CYP3A4 and DRV/Ritonavir (RTV) docking was performed using GOLD suite 5.8.

Results

Ethanol (20 mM) significantly decreased apparent half-life and increased degradation rate constant of RTV-boosted DRV but not for DRV alone. Similarly, ethanol exposure increased hepatic intrinsic clearance for RTV-boosted DRV with no significant influence on DRV alone. Ethanol showed a limited influence on intracellular total DRV exposure in the presence of RTV without altering maximum concentration (Cmax) values in HIV-infected monocytic cells. Ethanol alone elevated HIV replication but this effect was nullified with the addition of DRV or DRV + RTV. Additionally, inhibitory potency of DRV was significantly reduced in the presence of ethanol. Our docking results projected that ethanol increases the average distance between DRV and CYP3A4 heme, and alter the orientation of DRV-CYP3A4 binding.

Conclusions

Collectively these findings suggest that DRV metabolism is primarily influenced by ethanol in the liver, but has minor effect in HIV-residing monocytes.

Key words

antiretroviral therapy cytochrome P450 drug-drug interaction ethanol HIV 

Abbreviations

AUCtot

Area under the concentration-time curve

Cmax

The maximum concentration of a drug in the cells after dosing

CYP

Cytochrome P450

DRV

Darunavir

EVG

Elvitegravir

IC50

The 50% inhibitory concentration

Km

The Michaelis-Menten constant

LC-MS/MS

Liquid chromatography-tandem mass spectrometry

RTV

Ritonavir

Vmax

The maximal velocity

Notes

Acknowledgments and Disclosures

This research was supported by grants from the National Institute of Health to Santosh Kumar (NIAAA/NIH AA-022063) and Bernd Meibohm (OD/NIH S10OD016226), and from the National Natural Science Foundation of China to Weihua Li (Grant 81,373,328).

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Narasimha M. Midde
    • 1
    Email author
  • Yuqing Gong
    • 1
  • Theodore J. Cory
    • 2
  • Junhao Li
    • 3
  • Bernd Meibohm
    • 1
  • Weihua Li
    • 3
  • Santosh Kumar
    • 1
    Email author
  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of Tennessee Health Science CenterMemphisUSA
  2. 2.Department of Clinical Pharmacy, College of PharmacyUniversity of Tennessee Health Science Center,MemphisUSA
  3. 3.Shanghai Key Laboratory of New Drug Design, School of PharmacyEast China University of Science and Technology,ShanghaiChina

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