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

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.

The role of cytochrome P450 2E1 on ethanol-mediated oxidative stress and HIV replication in human monocyte-derived macrophages

“…Studies with HIV-1-infected macaques have shown increased viral load in the blood and cerebral compartments of chronic-drinking animals [8] . Moreover, previous reports from our lab suggest that ethanol reduced intracellular concentrations of antiretroviral drugs (elvitegravir, darunavir) in the HIV-1-infected U1 cell line [9] , [10] . Ethanol also increased HIV-1 replication despite the presence of elvitegravir [10] .…”

“…Furthermore, our laboratory has been studying the effect of alcohol consumption on antiretroviral drugs in the past few years. We have shown that the metabolism of darunavir, an important ARV drug, is influenced by ethanol, and has faster hepatic intrinsic clearance in the presence of a ritonavir-boosted darunavir combination [9] . Our previous studies have also shown that ethanol has the ability to interact with microsomal CYP3A4 and alter elvitegravir metabolism and HIV-1 replication in monocytic cells [44] .…”

Effects of alcohol on metabolism and toxicity of cocaine in rats

“…However, the overall effects of alcohol on CYP3A4 might be complicated. Interestingly, while chronic alcohol use results in the increase of CYP3A4 expression and, thus, indirectly increases the CYP3A4 activity, alcohol itself also binds with CYP3A4 in the active site to directly affect the CYP3A4 activity [32] . The CYP3A4-alcohol binding affinity ( K d ) was determined as 5.9 mM [33] .…”

An update on drug–drug interactions between antiretroviral therapies and drugs of abuse in HIV systems

“…They reported that this alcohol-induced alteration of elvitegravir concentrations were associated with the induction of CYP3A4, and the drug transporters MRP1 and MDR1. The same group also reported the effect of alcohol on a protease inhibitor, darunavir, and its effect on hepatic clearance, intracellular pharmacokinetics, HIV suppression of darunavir in liver microsomes and U1 cells [40]. They showed that alcohol decreases apparent half-life and hepatic intrinsic clearance of darunavir when alcohol was co-exposed with a commonly used pharmaco-enhancer, ritonavir.…”