Chu Yenju, Qin Chaolong, Feng Wanshan, Sheriston Charles, Jane Khor Yu, Medrano-Padial Concepción, Watson Birgit E, Chan Teddy, Ling Binhua, Stocks Michael J, Fischer Peter M, Gershkovich Pavel
School of Pharmacy, University of Nottingham, Nottingham, United Kingdom; Tri-Service General Hospital, Medical Supplies and Maintenance Office, National Defense Medical Centre, Taipei, Taiwan.
School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
Int J Pharm. 2021 Jun 1;602:120621. doi: 10.1016/j.ijpharm.2021.120621. Epub 2021 Apr 21.
The introduction of combination antiretroviral therapy (cART) led to substantial improvement in mortality and morbidity of HIV-1 infection. However, the poor penetration of antiretroviral agents to HIV-1 reservoirs limit the ability of the antiretroviral agents to eliminate the virus. Mesenteric lymph nodes (MLNs) are one of the main HIV-1 reservoirs in patients under suppressive cART. Intestinal lymphatic absorption pathway substantially increases the concentration of lipophilic drugs in mesenteric lymph and MLNs when they are co-administered with long-chain triglyceride (LCT). Chylomicrons (CM) play a crucial role in the intestinal lymphatic absorption as they transport drugs to the lymph lacteals rather than blood capillary by forming CM-drug complexes in the enterocytes. Thus, lipophilic antiretroviral drugs could potentially be delivered to HIV-1 reservoirs in MLNs by LCT-based formulation approach. In this study, protease inhibitors (PIs) were initially screened for their potential for intestinal lymphatic targeting using a computational model. The candidates were further assessed for their experimental affinity to CM. Tipranavir (TPV) was the only-candidate with substantial affinity to both artificial and natural CM in vitro and ex vivo. Pharmacokinetics and biodistribution studies were then performed to evaluate the oral bioavailability and intestinal lymphatic targeting of TPV in rats. The results showed similar oral bioavailability of TPV with and without co-administration of LCT vehicle. Although LCT-based formulation led to 3-fold higher concentrations of TPV in mesenteric lymph compared to plasma, the levels of the drug in MLNs were similar to plasma in both LCT-based and lipid-free formulation groups. Thus, LCT-based formulation approach alone was not sufficient for effective delivery of TPV to MLNs. Future efforts should be directed to a combined highly lipophilic prodrugs/lipid-based formulation approach to target TPV, other PIs and potentially other classes of antiretroviral agents to viral reservoirs within the mesenteric lymphatic system.
联合抗逆转录病毒疗法（cART）的引入使HIV-1感染的死亡率和发病率有了显著改善。然而，抗逆转录病毒药物对HIV-1储存库的穿透性较差，限制了其清除病毒的能力。肠系膜淋巴结（MLNs）是接受抑制性cART治疗患者的主要HIV-1储存库之一。当亲脂性药物与长链甘油三酯（LCT）共同给药时，肠道淋巴吸收途径会显著增加肠系膜淋巴和MLNs中亲脂性药物的浓度。乳糜微粒（CM）在肠道淋巴吸收中起关键作用，因为它们通过在肠细胞中形成CM-药物复合物将药物转运至淋巴乳糜管而非毛细血管。因此，亲脂性抗逆转录病毒药物有可能通过基于LCT的制剂方法递送至MLNs中的HIV-1储存库。在本研究中，首先使用计算模型筛选蛋白酶抑制剂（PIs）的肠道淋巴靶向潜力。进一步评估候选药物对CM的实验亲和力。替拉那韦（TPV）是唯一在体外和体内对人工和天然CM均具有显著亲和力的候选药物。随后进行了药代动力学和生物分布研究，以评估TPV在大鼠中的口服生物利用度和肠道淋巴靶向性。结果显示，无论是否与LCT载体共同给药，TPV的口服生物利用度相似。尽管基于LCT的制剂使肠系膜淋巴中TPV的浓度比血浆高3倍，但在基于LCT的制剂组和无脂质制剂组中，MLNs中的药物水平与血浆相似。因此，仅基于LCT的制剂方法不足以将TPV有效递送至MLNs。未来的努力应致力于采用联合的高亲脂性前药/基于脂质的制剂方法，将TPV、其他PIs以及可能的其他类抗逆转录病毒药物靶向肠系膜淋巴系统内的病毒储存库。
