Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
Fluids Barriers CNS. 2024 Jan 10;21(1):5. doi: 10.1186/s12987-023-00507-3.
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 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.
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 transport, suggesting a specificity for cocaine. Unexpectedly, cocaine did not breach the BBB, as permeability to albumin and 4 kDa FITC-dextran, as well as tight junction proteins and adhesion molecules remained unchanged. Rather, cocaine selectively decreased the pregnane-x receptor (PXR), but not constitutive androstane receptor (CAR). 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 that are required to facilitate biotransformation of ART prodrugs to their phosphorylated, pharmacologically active counterparts.
Our findings indicate that 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.
抗逆转录病毒疗法（ART）与血脑屏障（BBB）中的药物转运体和代谢酶之间的适当相互作用对于确保大脑获得足够的药物剂量以实现 HIV 抑制至关重要。这些蛋白受人口统计学和生活方式因素的调节，包括物质使用。虽然研究不足，但非法物质与 ART 共享药物转运和代谢途径，增加了药物相互作用的潜在风险。当考虑到大脑时，这一点尤其重要，因为与外周器官相比，大脑相对治疗不足，并且容易受到物质使用介导的损伤。
我们使用体外 BBB 模型来确定三种一线 ART 药物，恩曲他滨（FTC）、替诺福韦（TFV）和多替拉韦（DTG）在可卡因存在和不存在的情况下的外渗情况，可卡因作为我们的非法物质模型。评估可卡因对 BBB 完整性和通透性、药物转运体、代谢酶及其主转录调节剂的影响，以确定物质使用影响 ART 中枢神经系统（CNS）可用性的机制。
我们确定可卡因对 ART 外渗具有选择性影响，它增加了 FTC 穿过 BBB 的能力，同时降低了 TFV。穿过 BBB 的 DTG 浓度低于可量化限度。有趣的是，强效神经炎症调节剂脂多糖对 ART 转运没有影响，表明可卡因具有特异性。出乎意料的是，可卡因并没有穿透 BBB，因为白蛋白和 4 kDa FITC-葡聚糖以及紧密连接蛋白和粘附分子的通透性保持不变。相反，可卡因选择性地降低了孕烷 X 受体（PXR），但不降低组成型雄烷受体（CAR）。因此，药物转运体在 BBB 的内皮细胞中的表达和活性降低，包括 P-糖蛋白（P-gp）、乳腺癌耐药蛋白（BCRP）和多药耐药相关蛋白 4（MRP4）。此外，可卡因治疗后细胞色素 P450 3A4（CYP3A4）酶活性增加，同时表达降低。最后，可卡因调节了腺苷酸激酶，这对于将 ART 前药生物转化为磷酸化的、具有药理活性的对应物是必需的。
我们的研究结果表明，对于使用可卡因的 HIV 感染者的 CNS 治疗策略需要考虑更多因素，因为可卡因可能通过调节 BBB 中的药物转运和代谢途径来限制 ART 的疗效。
