Antiretroviral penetration and drug transporter concentrations in the spleens of three preclinical animal models and humans

Craig Sykes, Martina Kovarova, Lourdes Adamson, Leila Remling-Mulder, Paul Luciw, J. Victor Garcia, Ramesh Akkina, Jason R. Pirone, Philip C. Smith, Angela D.M. Kashubaa, Aaron S. Devanathan, John K. Fallon, Nicole R. White, Amanda P. Schauer, Brian Van Horne, Kimberly Blake

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 (huHSC-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.

Original languageEnglish (US)
Article numbere01384
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number10
DOIs
StatePublished - Oct 2020

Keywords

  • Antiretrovirals
  • Drug transporters
  • Pharmacokinetics
  • Sex differences
  • Spleen

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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