Cocaine regulates antiretroviral therapy CNS access through pregnane-x receptor-mediated drug transporter and metabolizing enzyme modulation at the blood brain barrier

作者：Rodnie Colón Ortiz, Stephen Knerler, Lisa B. Fridman, Alicia Mercado, A C Price, Jose J. Rosado‐Franco, Hannah Wilkins, Bianca Flores, Benjamin C. Orsburn, Dionna W. Williams · 发表于：Fluids and Barriers of the CNS · 年份：2024 · DOI：10.1186/s12987-023-00507-3 · 被引用次数：11 · 研究领域：HIV Research and Treatment、Drug Transport and Resistance Mechanisms、HIV/AIDS drug development and treatment

BACKGROUND: 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. METHODS: We used an in vitro model of the human BBB to determine the extravasation of three first-line ART drugs, emtricitabine (FTC), tenofovir (TFV), and dolutegravir (DTG), in the presence and absence of cocaine, which served as our illicit substance model. The impact of cocaine on BBB integrity and permeability, drug transporters, metabolizing enzymes, and their master transcriptional regulators were evaluated to determine the mechanisms by which substance use impacted ART central nervous system (CNS) availability. RESULTS: 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, the potent neuroinflammatory modulator, lipopolysaccharide, had no effect on ART...