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Antiretroviral Penetration and Drug Transporter Concentrations in the Spleens of Three Preclinical Animal Models and Humans.
Antimicrobial Agents and Chemotherapy ( IF 4.9 ) Pub Date : 2020-09-21 , DOI: 10.1128/aac.01384-20
Aaron S Devanathan 1 , John K Fallon 1 , Nicole R White 1 , Amanda P Schauer 1 , Brian Van Horne 1 , Kimberly Blake 1 , Craig Sykes 1 , Martina Kovarova 2 , Lourdes Adamson 3 , Leila Remling-Mulder 4 , Paul Luciw 3 , J Victor Garcia 2 , Ramesh Akkina 4 , Jason R Pirone 1 , Philip C Smith 1 , Angela D M Kashuba 2, 5
Affiliation  

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.

中文翻译:

三种临床前动物模型和人类脾脏中的抗逆转录病毒渗透性和药物转运蛋白浓度。

淋巴组织中足够的抗逆转录病毒(ARV)浓度对于最佳抗逆转录病毒治疗(ART)至关重要。尽管脾脏含有人体淋巴细胞的25%,但有关该器官中ARV渗透的数据很少。这项研究量化了总和未结合蛋白质的脾ARV浓度,并确定了药物转运蛋白,性别或感染状态是否是动物模型和人类中这些浓度的调节剂。两种人源化小鼠模型(HU-HSC-碎布[ Ñ = 36; 18 HIV阳性(HIV +)和18 HIV阴性(HIV -)]和骨髓-肝-胸腺[ Ñ = 13; 7 HIV +和6 HIV - ])和一个非人灵长类动物(NHP)模型(恒河猴[ ñ= 18; 10 SHIV +和8 SHIV - ])进行给药稳定状态与ARV组合。HIV +人脾(ñ= 14)来自国家NeuroAIDS组织协会的死后分析(给药后长达24小时)。通过液相色谱-串联质谱(LC-MS / MS)测量ARV浓度,通过LC-MS蛋白质组学测量药物转运蛋白浓度,并通过快速平衡透析确定NHP脾脏中的蛋白质结合。通常,小鼠的脾脏浓度在三个物种中最低。脾组织中的蛋白质结合率为6%至96%,而血浆中为76%至99%。NHP具有可量化的Mrp4,Bcrp和Ent1浓度,而人类具有可量化的ENT1浓度。没有一个与组织抗逆转录病毒浓度显着相关。感染状况或性别也没有明显影响。通过这些剂量策略,NHP脾脏渗透最类似于人类。
更新日期:2020-09-21
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