Antiretroviral Penetration and Drug Transporter Concentrations in the Spleens of Three Preclinical Animal Models and Humans
| Autor: | John K. Fallon, Lourdes Adamson, Angela D. M. Kashuba, Craig Sykes, Jason R. Pirone, Ramesh Akkina, Martina Kovarova, Amanda P. Schauer, Kimberly Blake, Leila Remling-Mulder, Philip C. Smith, Brian Van Horne, Paul A. Luciw, Aaron S. Devanathan, J. Victor Garcia, Nicole White |
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| Rok vydání: | 2020 |
| Předmět: |
Drug
Anti-HIV Agents media_common.quotation_subject HIV Infections Spleen Pharmacology Mice 03 medical and health sciences Pharmacokinetics Tandem Mass Spectrometry Blood plasma medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans Pharmacology (medical) Dosing 030304 developmental biology media_common 0303 health sciences biology 030306 microbiology business.industry virus diseases Transporter biology.organism_classification Macaca mulatta Neoplasm Proteins Rhesus macaque Infectious Diseases medicine.anatomical_structure Pharmaceutical Preparations Splenic Tissue Models Animal business Chromatography Liquid |
| Zdroj: | Antimicrob Agents Chemother |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | 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 [n = 36; 18 HIV-positive (HIV(+)) and 18 HIV-negative (HIV(−))] and bone marrow-liver-thymus [n = 13; 7 HIV(+) and 6 HIV(−)]) and one nonhuman primate (NHP) model (rhesus macaque [n = 18; 10 SHIV(+) and 8 SHIV(−)]) were dosed to steady state with ARV combinations. HIV(+) human spleens (n = 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. |
| Databáze: | OpenAIRE |
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