Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, UNMC, Omaha, NE, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, UNMC, Omaha, NE, USA.
J Antimicrob Chemother. 2019 Oct 1;74(10):2974-2978. doi: 10.1093/jac/dkz273.
The secondary lymphoid tissues (LTs), lymph nodes (LNs) and gut-associated lymphoid tissue (GALT) are considered reservoirs for HIV. Antiretrovirals (ARVs) have lower penetration into LT. In vitro models predictive of ARV LT penetration have not been established.
To develop an in vitro model of LT bioavailability using human lymphoid endothelial cells (HLECs) and investigate its predictability with in vivo pharmacokinetic (PK) studies in mice.
ARV bioavailability in HLECs was evaluated at the maximum plasma concentration (Cmax) observed in HIV-infected patients. ARVs were: abacavir, atazanavir, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, maraviroc, raltegravir, rilpivirine, ritonavir, tenofovir disoproxil fumarate and the PK booster cobicistat. The LT PK of representative drugs showing high (efavirenz), intermediate (dolutegravir) and low (emtricitabine) HLEC bioavailability was investigated in BALB/c mice given 50/10/30 mg/kg efavirenz/dolutegravir/emtricitabine orally, daily for 3 days. The concordance of in vitro and in vivo ARV bioavailability was examined.
ARVs showed high (>67th percentile; rilpivirine, efavirenz, elvitegravir and cobicistat), intermediate (67th-33rd percentile; ritonavir, tenofovir disoproxil fumarate, dolutegravir and maraviroc) and low (<33rd percentile; atazanavir, darunavir, raltegravir, emtricitabine and abacavir) HLEC bioavailability. The hierarchy of efavirenz, dolutegravir and emtricitabine bioavailability in LN, gut and brain tissues of mice was: efavirenz>dolutegravir>emtricitabine.
ARVs displayed distinct HLEC penetration patterns. PK studies of representative ARVs in LT of mice were concordant with HLEC bioavailability. These findings support further development of this approach and its translational predictability in humans.
次级淋巴组织（LTs）、淋巴结（LNs）和肠道相关淋巴组织（GALT）被认为是 HIV 的储库。抗逆转录病毒药物（ARVs）在 LT 中的穿透率较低。尚未建立预测 ARV LT 穿透率的体外模型。
使用人淋巴内皮细胞（HLEC）建立 LT 生物利用度的体外模型，并研究其与小鼠体内药代动力学（PK）研究的预测性。
在感染 HIV 的患者中观察到的最大血浆浓度（Cmax）时，评估 ARV 在 HLEC 中的生物利用度。研究的 ARVs 包括：阿巴卡韦、阿扎那韦、达芦那韦、度鲁特韦、依非韦伦、艾维雷韦、恩曲他滨、马拉维若、拉替拉韦、利匹韦林、利托那韦、替诺福韦二吡呋酯和 PK 增强剂考比司他。在给予 BALB/c 小鼠 50/10/30mg/kg 依非韦伦/度鲁特韦/恩曲他滨口服，每日 3 天的情况下，研究了显示高（依非韦伦）、中（度鲁特韦）和低（恩曲他滨）HLEC 生物利用度的代表性药物的 LT PK。检查了体外和体内 ARV 生物利用度的一致性。
ARVs 显示出高（>第 67 百分位；利匹韦林、依非韦伦、艾维雷韦和考比司他）、中（第 67-33 百分位；利托那韦、替诺福韦二吡呋酯、度鲁特韦和马拉维若）和低（<第 33 百分位；阿扎那韦、达芦那韦、拉替拉韦、恩曲他滨和阿巴卡韦）HLEC 生物利用度。在小鼠的 LN、肠道和脑组织中，依非韦伦、度鲁特韦和恩曲他滨的生物利用度顺序为：依非韦伦>度鲁特韦>恩曲他滨。
ARVs 显示出不同的 HLEC 穿透模式。在小鼠 LT 中代表性 ARV 的 PK 研究与 HLEC 生物利用度一致。这些发现支持进一步开发这种方法及其在人类中的转化预测性。
