Woodward D K, Hatton J, Ensom M H, Young B, Dempsey R, Clifton G D
University of Kentucky Medical Center, College of Pharmacy, Lexington, USA.
Pharmacotherapy. 1998 Sep-Oct;18(5):1062-8.
To test the hypothesis that changes in alpha1-acid glycoprotein (AAG) concentration alter central nervous system (CNS) drug distribution after subarachnoid hemorrhage.
Two-phase, prospective study.
University-associated medical center.
Twenty-one patients with subarachnoid hemorrhage.
In phase I, serum AAG concentrations of patients with subarachnoid hemorrhage were measured serially and compared with those in 21 controls undergoing elective neurosurgical procedures. In phase II, nimodipine was the pharmacologic probe to determine the relationship between drug distribution into the CNS and changes in AAG concentration.
Serum and cerebrospinal fluid (CSF) samples were collected from patients with subarachnoid hemorrhage treated with nimodipine and used to measure total and unbound drug concentrations. Concentrations of AAG were 39% higher in patients than in controls preoperatively. They decreased significantly by 24 hours after surgery in patients and increased in controls. In both groups the concentrations were higher than reported normal values. During the period of reduced AAG concentration, calculated unbound nimodipine concentrations were 3-fold higher (p<0.05) than at later periods, with a trend toward higher total concentrations. Overall, mean CSF nimodipine concentration was 6.4% of mean serum total concentration. The CSF concentrations decreased as AAG concentrations increased, independent of serum concentrations (r = -0.52, p<0.02).
Concentrations of AAG change after subarachnoid hemorrhage and are transiently influenced by surgery. Unbound drug concentration increases when AAG concentrations decrease, whereas CSF concentrations decrease when AAG concentrations increase. These preliminary findings suggest that changes in AAG concentrations can alter unbound serum nimodipine concentrations and may affect CSF drug distribution.
检验蛛网膜下腔出血后α1-酸性糖蛋白（AAG）浓度变化会改变中枢神经系统（CNS）药物分布这一假设。
两阶段前瞻性研究。
大学附属医院。
21例蛛网膜下腔出血患者。
在第一阶段，连续测量蛛网膜下腔出血患者的血清AAG浓度，并与21例接受择期神经外科手术的对照组患者的血清AAG浓度进行比较。在第二阶段，使用尼莫地平作为药理学探针，以确定药物向中枢神经系统的分布与AAG浓度变化之间的关系。
收集接受尼莫地平治疗的蛛网膜下腔出血患者的血清和脑脊液（CSF）样本，用于测量总药物浓度和游离药物浓度。患者术前AAG浓度比对照组高39%。术后24小时患者的AAG浓度显著下降，而对照组的AAG浓度升高。两组的浓度均高于报告的正常值。在AAG浓度降低期间，计算得出的游离尼莫地平浓度比后期高3倍（p<0.05），总浓度也有升高趋势。总体而言，脑脊液中尼莫地平的平均浓度为血清总平均浓度的6.4%。脑脊液浓度随AAG浓度升高而降低，与血清浓度无关（r = -0.52，p<0.02）。
蛛网膜下腔出血后AAG浓度会发生变化，并受到手术的短暂影响。当AAG浓度降低时，游离药物浓度升高；当AAG浓度升高时，脑脊液浓度降低。这些初步研究结果表明，AAG浓度的变化可改变血清中游离尼莫地平的浓度，并可能影响脑脊液中的药物分布。
