Distribution of lamivudine into lymph node HIV reservoir

Wong, Abigail; Chu, YenJu; Chen, Haojie; Feng, Wanshan; Ji, Liuhang; Qin, Chaolong; Stocks, Michael J.; Marlow, Maria; Gershkovich, Pavel

Abstract

Efficient delivery of antiretroviral agents to lymph nodes is important to decrease the size of the HIV reservoir within the lymphatic system. Lamivudine (3TC) is used in first-line regimens for the treatment of HIV. As a highly hydrophilic small molecule, 3TC is not predicted to associate with chylomicrons and therefore should have negligible uptake into intestinal lymphatics following oral administration. Similarly, negligible amounts of 3TC are predicted to be transported into peripheral lymphatics following subcutaneous (SC) injection due to the faster flow rate of blood in comparison to lymph. In this work, we performed pharmacokinetic and biodistribution studies of 3TC in rats following oral lipid-based, oral lipid-free, SC, and intravenous (IV) administrations. In the oral administration studies, mesenteric lymph nodes (MLNs) had significantly higher 3TC concentrations compared to other lymph nodes, with mean tissue:serum ratios ranging from 1.4 to 2.9. However, cells and chylomicrons found in mesenteric lymph showed low-to-undetectable concentrations. In SC studies, administration-side (right) draining inguinal and popliteal lymph nodes had significantly higher concentrations (tissue:serum ratios as high as 3.2) than corresponding left-side nodes. In IV studies, lymph nodes had lower mean tissue:serum ratios ranging from 0.9 to 1.4. We hypothesize that following oral or SC administration, slower permeation of this hydrophilic molecule into blood capillaries may result in considerable passive 3TC penetration into lymphatic vessels. Further studies will be needed to clarify the mechanism of delivery of 3TC and similar antiretroviral drugs into the lymph nodes.

Citation

Wong, A., Chu, Y., Chen, H., Feng, W., Ji, L., Qin, C., Stocks, M. J., Marlow, M., & Gershkovich, P. (2023). Distribution of lamivudine into lymph node HIV reservoir. International Journal of Pharmaceutics, 648, Article 123574. https://doi.org/10.1016/j.ijpharm.2023.123574

• Journal Article Type: Article
• Acceptance Date: Nov 2, 2023
• Online Publication Date: Nov 15, 2023
• Publication Date: Dec 15, 2023
• Deposit Date: Apr 3, 2025
• Publicly Available Date: Apr 8, 2025
• Journal: International Journal of Pharmaceutics
• Print ISSN: 0378-5173
• Electronic ISSN: 1873-3476
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 648
• Article Number: 123574
• DOI: https://doi.org/10.1016/j.ijpharm.2023.123574
• Keywords: Lamivudine, Chylomicrons, Intestinal lymphatic transport, Mesenteric lymph nodes, Peripheral lymph nodes, HIV reservoirs
• Public URL: https://nottingham-repository.worktribe.com/output/27089390
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S037851732300995X?via%3Dihub
• Additional Information: This article is maintained by: Elsevier; Article Title: Distribution of lamivudine into lymph node HIV reservoir; Journal Title: International Journal of Pharmaceutics; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.ijpharm.2023.123574; Content Type: article; Copyright: © 2023 The Author(s). Published by Elsevier B.V.