Antiretroviral Penetration and Drug Transporter Concentrations in the Spleens of Three Preclinical Animal Models and Humans.
Title | Antiretroviral Penetration and Drug Transporter Concentrations in the Spleens of Three Preclinical Animal Models and Humans. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Devanathan, AS, Fallon, JK, White, NR, Schauer, AP, Van Horne, B, Blake, K, Sykes, C, Kovarova, M, Adamson, L, Remling-Mulder, L, Luciw, P, J Garcia, V, Akkina, R, Pirone, JR, Smith, PC, Kashuba, ADM |
Journal | Antimicrob Agents Chemother |
Volume | 64 |
Issue | 10 |
Date Published | 2020 09 21 |
ISSN | 1098-6596 |
Keywords | External |
Abstract | Adequate antiretroviral (ARV) concentrations in lymphoid tissues are critical for optimal antiretroviral therapy (ART). While the spleen contains 25% of the body's lymphocytes, there are minimal data on ARV penetration in this organ. This study quantified total and protein-unbound splenic ARV concentrations and determined whether drug transporters, sex, or infection status were modifiers of these concentrations in animal models and humans. Two humanized mice models (hu-HSC-Rag [ = 36; 18 HIV-positive (HIV) and 18 HIV-negative (HIV)] and bone marrow-liver-thymus [ = 13; 7 HIV and 6 HIV]) and one nonhuman primate (NHP) model (rhesus macaque [ = 18; 10 SHIV and 8 SHIV]) were dosed to steady state with ARV combinations. HIV human spleens ( = 14) from the National NeuroAIDS Tissue Consortium were analyzed postmortem (up to 24 h postdose). ARV concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), drug transporter concentrations were measured with LC-MS proteomics, and protein binding in NHP spleens was determined by rapid equilibrium dialysis. Mice generally had the lowest splenic concentrations of the three species. Protein binding in splenic tissue was 6 to 96%, compared to 76 to 99% in blood plasma. NHPs had quantifiable Mrp4, Bcrp, and Ent1 concentrations, and humans had quantifiable ENT1 concentrations. None significantly correlated with tissue ARV concentrations. There was also no observable influence of infection status or sex. With these dosing strategies, NHP splenic penetration most closely resembled that of humans. These data can inform tissue pharmacokinetic scaling to humans to target HIV reservoirs by identifying important species-related differences. |
DOI | 10.1128/AAC.01384-20 |
Alternate Journal | Antimicrob Agents Chemother |
PubMed ID | 32661005 |
PubMed Central ID | PMC7508597 |
Grant List | U24 MH100929 / MH / NIMH NIH HHS / United States U24 MH100931 / MH / NIMH NIH HHS / United States U24 MH100928 / MH / NIMH NIH HHS / United States P51 OD011107 / OD / NIH HHS / United States R01 AI111891 / AI / NIAID NIH HHS / United States T32 GM086330 / GM / NIGMS NIH HHS / United States U24 MH100930 / MH / NIMH NIH HHS / United States P30 AI050410 / AI / NIAID NIH HHS / United States |