Narasimha M Midde1, Yuqing Gong2, Theodore J Cory3, Junhao Li4, Bernd Meibohm2, Weihua Li4, Santosh Kumar5. 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Ave, Rm 456, Memphis, TN, 38163, USA. nmidde@uthsc.edu. 2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Ave, Rm 456, Memphis, TN, 38163, USA. 3. Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center,, Memphis, TN, 38163, USA. 4. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology,, Shanghai, 200237, China. 5. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Ave, Rm 456, Memphis, TN, 38163, USA. ksantosh@uthsc.edu.
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.
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 CYP3A4heme, 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.
Authors: Anusha Ande; Namita Sinha; P S S Rao; Carole P McArthur; Leo Ayuk; Paul N Achu; Annette Njinda; Anil Kumar; Santosh Kumar Journal: AIDS Res Ther Date: 2015-09-22 Impact factor: 2.250
Authors: Lei Wang; Mary C Casey; Sanjeev Kumar V Vernekar; Rajkumar Lalji Sahani; Jayakanth Kankanala; Karen A Kirby; Haijuan Du; Atsuko Hachiya; Huanchun Zhang; Philip R Tedbury; Jiashu Xie; Stefan G Sarafianos; Zhengqiang Wang Journal: Eur J Med Chem Date: 2020-07-19 Impact factor: 6.514