Antiretroviral concentrations and surrogate measures of efficacy in the brain tissue and CSF of preclinical species.
Antiretroviral concentrations and surrogate measures of efficacy in the brain tissue and CSF of preclinical species.
复制标题
DOI：
10.1080/00498254.2018.1539278
复制
发表时间：
2019-10
期刊：
影响因子：
--
通讯作者：
Kashuba ADM
中科院分区：
文献类型：
--
作者：
Srinivas N;Rosen EP;Gilliland WM Jr;Kovarova M;Remling-Mulder L;De La Cruz G;White N;Adamson L;Schauer AP;Sykes C;Luciw P;Garcia JV;Akkina R;Kashuba ADM
1. 脑脊液（CSF）中的抗逆转录病毒浓度被用作脑组织的替代物，尽管支持这一点的数据很少。我们量化了临床前模型中脑组织中的抗逆转录病毒药物，将其与脑脊液进行比较，并计算了非人灵长类动物 (NHP) 脑组织的 90% 抑制商 (IQ90)。通过质谱成像（MSI）进行依非韦伦的空间分布。 2. 来自两种人源化小鼠模型（造血干细胞/RAG2-，n=36；骨髓-肝脏-胸腺/BLT，n=13）和NHP模型（恒河猴，n=18）的HIV或RT-SHIV感染和未感染动物接受六种抗逆转录病毒药物给药。尸检时收集脑组织、脑脊液（NHP）和血浆。通过LC-MS/MS测量药物浓度。快速平衡透析测定 NHP 脑中的蛋白质结合。 3. 大多数抗逆转录病毒药物在人源化小鼠中的脑组织渗透率比 NHP 低 10 倍以上 (p<0.02)。 NHP CSF 浓度比脑组织低 13 倍以上（p<0.02），除依非韦伦外，一致性较差（r=0.91，p=0.001）。尽管脑组织蛋白结合率为 97%，依非韦伦在所有动物中均实现了 IQ90>1，并且白质浓度比灰质浓度高出 2 倍。 4. 除拉替拉韦外，所有抗逆转录病毒药物的脑组织渗透率在动物模型之间存在差异，应避免推断模型之间的脑组织浓度。除依非韦伦外，脑脊液不能替代脑组织浓度。
1. Antiretroviral concentrations in cerebrospinal fluid (CSF) are used as surrogate for brain tissue, although sparse data support this. We quantified antiretrovirals in brain tissue across preclinical models, compared them to CSF, and calculated 90% inhibitory quotients (IQ90) for nonhuman primate (NHP) brain tissue. Spatial distribution of efavirenz was performed by mass-spectrometry imaging (MSI). 2. HIV or RT-SHIV-infected and uninfected animals from two humanized mouse models (hemopoietic-stem cell/RAG2-, n=36; bone marrow-liver-thymus/BLT, n=13) and an NHP model (rhesus macaque, n=18) were dosed with six antiretrovirals. Brain tissue, CSF (NHPs) and plasma were collected at necropsy. Drug concentrations were measured by LC-MS/MS. Rapid equilibrium dialysis determined protein binding in NHP brain. 3. Brain tissue penetration of most antiretrovirals were >10-fold lower (p<0.02) in humanized mice than NHPs. NHP CSF concentrations were >13-fold lower (p<0.02) than brain tissue with poor agreement except for efavirenz (r=0.91, p=0.001). Despite 97% brain tissue protein binding, efavirenz achieved IQ90>1 in all animals and 2-fold greater white versus grey matter concentration. 4. Brain tissue penetration varied across animal models for all antiretrovirals except raltegravir, and extrapolating brain tissue concentrations between models should be avoided. With the exception of efavirenz, CSF is not a surrogate for brain tissue concentrations.
登录
查看更多内容
影响因子：
11.8
作者：
Calcagno, Andrea;Simiele, Marco;Bonora, Stefano
通讯作者：
Bonora, Stefano
DOI：
10.1038/nrmicro2911
发表时间：
2012-12
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.1
作者：
Farhadian S;Patel P;Spudich S
通讯作者：
Spudich S
影响因子：
4.8
作者：
Anderson, Kyle W.;Mast, Natalia;Pikuleva, Irina A.
通讯作者：
Pikuleva, Irina A.
DOI：
10.1007/s13361-014-0884-1
发表时间：
2014-12-01
影响因子：
3.2
作者：
Barry, Jeremy A.;Robichaud, Guillaume;Muddiman, David C.
通讯作者：
Muddiman, David C.