Nicotine and cotinine increases the brain penetration of saquinavir in rat
Nicotine and cotinine increases the brain penetration of saquinavir in rat
复制标题
DOI：
10.1111/j.1471-4159.2010.07054.x
复制
发表时间：
2010-12-01
影响因子：
4.7
通讯作者：
Lockman, Paul R.
中科院分区：
文献类型：
--
作者：
Manda, Vamshi K.;Mittapalli, Rajendar K.;Lockman, Paul R.
血脑屏障（BBB）的内皮紧密连接和外排转运蛋白显著限制了许多药物在脑内的蓄积，包括蛋白酶抑制剂如沙奎那韦。胆碱能激动剂尼古丁是世界上最常用的药物之一，在人类免疫缺陷病毒人群中的发病率甚至更高（接近70%）。我们研究了尼古丁及其主要代谢产物可替宁改变沙奎那韦大鼠脑摄取的能力。尼古丁和可替宁在药理浓度匹配的吸烟者，增加大脑沙奎那韦摄取的两倍。与烟碱受体拮抗剂和被动渗透性标记物的共灌注表明，该效应不是由受体激活或BBB渗透性破坏引起的。转运抑制研究表明，脑内沙奎那韦摄取受多种外排转运蛋白、P-糖蛋白（P-gp）、乳腺癌耐药蛋白和多药耐药相关蛋白的限制。使用经典P-gp底物罗丹明123的原位灌注和体外实验将尼古丁的作用与BBB P-gp转运的抑制联系起来。在长期14天尼古丁给药动物中证实了体内效应。这些数据表明，尼古丁增加抗逆转录病毒药物暴露于大脑，并可能代表一个显着的体内药物相互作用在BBB。虽然这可能会轻微受益CNS抗逆转录病毒疗效，但也可能使大脑暴露于潜在的严重神经毒性。
P>Endothelial tight junctions and efflux transporters of the blood-brain barrier (BBB) significantly limit brain accumulation of many drugs, including protease inhibitors such as saquinavir. The cholinergic agonist nicotine is one of the most commonly used drugs in the world and the incidence is even higher in the human immune deficiency virus population (similar to 70%). We examined the ability of nicotine and its primary metabolite cotinine to modify brain uptake of saquinavir in rats. Both nicotine and cotinine at pharmacological concentrations matching those in smokers, increased brain saquinavir uptake by two fold. Co-perfusion with nicotinic receptor antagonists and passive permeability markers showed that the effect was not caused by receptor activation or BBB permeability disruption. Transport inhibition studies demonstrated that brain saquinavir uptake is limited by multiple efflux transporters, P-glycoprotein (P-gp), breast cancer resistance protein and multidrug resistance-associated protein. In situ perfusion and in vitro experiments using a classical P-gp substrate rhodamine 123 linked the effect of nicotine to inhibition of BBB P-gp transport. The effect was confirmed in vivo in chronic 14 day nicotine administration animals. These data suggest nicotine increases antiretroviral drug exposure to brain and may represent a significant in vivo drug-drug interaction at the BBB. Although this may slightly benefit CNS antiretroviral efficacy, it may also expose the brain to potential serious neurotoxicity.