Nevirapine uptake into the central nervous system of the guinea pig: An in situ brain perfusion study
Nevirapine uptake into the central nervous system of the guinea pig: An in situ brain perfusion study
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DOI：
10.1124/jpet.105.098459
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发表时间：
2006-05-01
影响因子：
3.5
通讯作者：
Thomas, SA
中科院分区：
文献类型：
--
作者：
Gibbs, JE;Gaffen, Z;Thomas, SA
人类免疫缺陷病毒（HIV）在中枢神经系统（CNS）中的存在与HIV-1相关性痴呆（HAD）的发生有关，HAD是HIV相关死亡的主要原因。为了根除CNS中的HIV，抗HIV药物需要以治疗浓度到达脑和脑脊液（CSF）。这涉及通过血脑屏障和血CSF屏障。本研究采用完善的豚鼠原位脑灌注模型，研究奈韦拉平[6 H-双吡啶并（3，2-B：2 '，3'-e）（1，4）二氮卓-6酮，11-环丙基-5，11-二氢-4-甲基]（一种非核苷逆转录酶抑制剂（NNRTI））是否可在CNS中有效蓄积。[ H-3]奈韦拉平与[ C-14]甘露醇（一种血管/细胞旁渗透性标记物）通过颈动脉共灌注长达30分钟，并测量脑、CSF和脉络丛中的蓄积。[ H-3]奈韦拉平在大脑中的摄取量大于[ C-14]甘露醇的摄取量，表明其显著穿过血脑屏障并蓄积至大脑中（这一点通过毛细血管耗竭和高效液相色谱分析得到进一步证实）。同样，与[ C-14]甘露醇相比，[ H-3]奈韦拉平显示出更强的穿过血-CSF屏障并在CSF中蓄积的能力。[ H-3]奈韦拉平的CNS蓄积不受100 μ M奈韦拉平的影响，表明可通过扩散穿过血脑屏障。此外，与100 μ M依法韦仑[2 H-3，1-苯并恶嗪-2-酮，6-氯-4-（环丙基乙炔基）1，4-二氢-4-（三氟甲基）-，（4S）-;另一种NNRTI]共灌注未显著改变[ H-3]奈韦拉平的CNS蓄积，表明在联合治疗中加入该药物不会改变奈韦拉平在CNS中的疗效。总之，这些数据表明，这种抗HIV药物应该有利于在CNS内根除HIV和随后治疗HAD。
The presence of human immunodeficiency virus ( HIV) in the central nervous system ( CNS) is associated with the development of HIV-1-associated dementia ( HAD), a major cause of HIV-related mortality. To eradicate HIV in the CNS, anti-HIV drugs need to reach the brain and cerebrospinal fluid ( CSF) in therapeutic concentrations. This involves passage through the blood-brain and blood-CSF barriers. Using a well established guinea pig in situ brain perfusion model, this study investigated whether nevirapine [ 6H-dipyrido( 3,2-b:2',3'-e)( 1,4) diazepin-6one, 11-cyclopropyl-5,11-dihydro-4-methyl], a non-nucleoside reverse transcriptase inhibitor ( NNRTI), could effectively accumulate in the CNS. [ H-3] Nevirapine was coperfused with [ C-14] mannitol ( a vascular/paracellular permeability marker) through the carotid arteries for up to 30 min, and accumulation in the brain, CSF, and choroid plexus was measured. [ H-3] Nevirapine uptake into the cerebrum was greater than uptake of [ C-14] mannitol, indicating significant passage across the bloodbrain barrier and accumulation into the brain ( this was further confirmed with capillary depletion and high-performance liquid chromatography analyses). Likewise, [ H-3] nevirapine showed a great ability to cross the blood-CSF barrier and accumulate in the CSF, compared with [ C-14] mannitol. The CNS accumulation of [ H-3] nevirapine was unaffected by 100 mu M nevirapine, suggesting that passage across the blood-brain barrier can occur by diffusion. Furthermore, coperfusion with 100 mu M efavirenz [ 2H-3,1-benzoxazin-2-one, 6-chloro-4-( cyclopropylethynyl)1,4-dihydro-4-(trifluoromethyl)-, ( 4S)-; another NNRTI] did not significantly alter CNS accumulation of [ H-3] nevirapine, indicating that the efficacy of nevirapine in the CNS would not be altered by the addition of this drug to a combination therapy. Together, these data indicate that this anti-HIV drug should be beneficial in the eradication of HIV within the CNS and the subsequent treatment of HAD.