Cocaine Regulates Antiretroviral Therapy CNS Access Through Pregnane-X Receptor-Mediated Drug Transporter and Metabolizing Enzyme Modulation at the Blood Brain Barrier

Abstract ID 101166 Poster Board 532 Appropriate interactions between antiretroviral therapies (ART) and drug transporters and metabolizing enzymes at the blood brain barrier (BBB) are critical to ensure adequate dosing of the brain to achieve HIV suppression. These proteins are modulated by demographic and lifestyle factors, including substance use. While understudied, illicit substances share drug transport and metabolism pathways with ART, increasing the potential for adverse drug:drug interactions. This is particularly important when considering the brain as it is relatively undertreated compared to peripheral organs and is vulnerable to substance use-mediated damage. We used an in vitro model of the human BBB to determine the extravasation of emtricitabine (FTC), tenofovir (TFV), and dolutegravir (DTG), in the presence and absence of cocaine. The impact of cocaine on BBB integrity and permeability, drug transporters, metabolizing enzymes, and their transcriptional regulators were evaluated. We determined that cocaine had a selective impact on ART extravasation, where it increased FTC's ability to cross the BBB while decreasing TFV. DTG concentrations that passed the BBB were below quantifiable limits. Interestingly, lipopolysaccharide had no effect on ART transport. Unexpectedly, cocaine did not breach the BBB, as permeability to albumin and junctional proteins remained unchanged. Rather, cocaine selectively decreased the pregnane-x receptor (PXR), but not constitutive androstane receptor. Consequently, drug transporter expression and activity decreased in endothelial cells of the BBB, including p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 4 (MRP4). Further, cytochrome P450 3A4 (CYP3A4) enzymatic activity increased following cocaine treatment that coincided with decreased expression. Finally, cocaine modulated adenylate kinases are required to facilitate biotransformation of ART prodrugs to their phosphorylated, pharmacologically active counterparts. Our findings indicate additional considerations are needed in CNS HIV treatment strategies for people who use cocaine, as it may limit ART efficacy through regulation of drug transport and metabolizing pathways at the BBB.