Roberts Derek J, Goralski Kerry B, Renton Kenneth W, Julien Lisa C, Webber Adam M, Sleno Lekha, Volmer Dietrich A, Hall Richard I
Division of Critical Care Medicine, Department of Medicine and Department of Anesthesia, Queen Elizabeth II Health Sciences Centre and Faculty of Medicine, Halifax, NS, Canada.
Crit Care Med. 2009 Oct;37(10):2767-74. doi: 10.1097/CCM.0b013e3181b755d5.
In animals, central nervous system inflammation increases drug accumulation in the brain partly due to a loss of central nervous system drug efflux transporter function at the blood-brain barrier. To determine whether a similar loss of active drug efflux occurs in humans after acute inflammatory brain injury.
Observational human pharmacokinetic study.
Medical-surgical-neurosurgical intensive care unit at a university-affiliated, Canadian tertiary care center.
Patients with acute inflammatory brain injury, including subarachnoid hemorrhage (n = 10), intracerebral and/or intraventricular hemorrhage (n = 4), or closed head trauma (n = 2) who received morphine intravenously after being fitted with cerebrospinal fluid ventriculostomy and peripheral arterial catheters.
We correlated the cerebrospinal fluid distribution of morphine, morphine-3-glucuronide, and morphine-6-glucuronide with the cerebrospinal fluid and plasma concentration of the proinflammatory cytokine interleukin-6 and the passive marker of blood-brain barrier permeability, albumin.
Acute brain injury produced a robust inflammatory response in the central nervous system as reflected by the elevated concentration of interleukin-6 in cerebrospinal fluid. Penetration of morphine metabolites into the central nervous system increased in proportion to the neuroinflammatory response as demonstrated by the positive correlation between cerebrospinal fluid interleukin-6 exposure and the area under the curve cerebrospinal fluid/plasma ratio for morphine-3-glucuronide (r = .49, p < .001) and morphine-6-glucuronide (r = .51, p < .001). In contrast, distribution of morphine into the brain was not linked with cerebrospinal fluid interleukin-6 exposure (r = .073, p = .54). Albumin concentrations in plasma and cerebrospinal fluid were consistently in the normal range, indicating that the physical integrity of the blood-brain barrier was likely undisturbed.
Our results suggest that central nervous system inflammation following acute brain injury may selectively inhibit the activity of specific drug efflux transporters within the blood-brain barrier. This finding may have significant implications for patients with neuroinflammatory conditions when administered centrally acting drugs normally excluded from the brain by such transporters.
在动物中，中枢神经系统炎症会增加药物在脑内的蓄积，部分原因是血脑屏障处中枢神经系统药物外排转运体功能丧失。为了确定急性炎症性脑损伤后人类是否也会出现类似的活性药物外排丧失情况。
观察性人体药代动力学研究。
加拿大一所大学附属三级护理中心的内科-外科-神经外科重症监护病房。
急性炎症性脑损伤患者，包括蛛网膜下腔出血（n = 10）、脑内和/或脑室内出血（n = 4）或闭合性颅脑损伤（n = 2），这些患者在置入脑脊液脑室造瘘管和外周动脉导管后接受静脉注射吗啡。
我们将吗啡、吗啡-3-葡萄糖醛酸苷和吗啡-6-葡萄糖醛酸苷在脑脊液中的分布与促炎细胞因子白细胞介素-6的脑脊液和血浆浓度以及血脑屏障通透性的被动标志物白蛋白进行了关联分析。
急性脑损伤在中枢神经系统产生了强烈的炎症反应，脑脊液中白细胞介素-6浓度升高即反映了这一点。吗啡代谢产物进入中枢神经系统的程度与神经炎症反应成比例增加，脑脊液白细胞介素-6暴露量与吗啡-3-葡萄糖醛酸苷脑脊液/血浆曲线下面积比值呈正相关（r = 0.49，p < 0.001）以及与吗啡-6-葡萄糖醛酸苷呈正相关（r = 0.51，p < 0.001）即证明了这一点。相比之下，吗啡在脑内的分布与脑脊液白细胞介素-6暴露量无关（r = 0.073，p = 0.54）。血浆和脑脊液中的白蛋白浓度始终在正常范围内，表明血脑屏障的物理完整性可能未受干扰。
我们的结果表明，急性脑损伤后的中枢神经系统炎症可能会选择性抑制血脑屏障内特定药物外排转运体的活性。这一发现对于患有神经炎症性疾病且正在使用通常会被此类转运体阻止进入脑内的中枢作用药物的患者可能具有重要意义。
