Jochemsen R, Van Beusekom B R, Spoelstra P, Janssens A R, Breimer D D
Br J Clin Pharmacol. 1983 Mar;15(3):295-302. doi: 10.1111/j.1365-2125.1983.tb01502.x.
The effect of age and liver cirrhosis on the pharmacokinetics of i.v. administered nitrazepam was studied in nine healthy relatively young subjects (age 22-49 years), eight healthy elderly (age 67-76 years) and 12 patients with alcoholic liver cirrhosis (age 39-66 years). The elimination half-life of nitrazepam in the elderly subjects was longer than in the young ones but the difference did not reach statistical significance. Mean values (ranges) were 38 (26-64) h and 26 (19-31) h respectively. The increase in elimination half-life was primarily due to an increase in volume of distribution, mean values (ranges) being 2.93 (1.96-5.33) l/kg and 1.89 (1.44-2.23) l/kg in the elderly and young groups respectively ( < 0.05). The protein unbound fraction of nitrazepam tended to be higher in the elderly subjects, although the difference between the two age groups was not significant: 13.9 (11.5-15.4)% and 13.0 (11.0-15.9)% in elderly and young respectively. Age had no effect on the clearance of total nitrazepam nor on the clearance of unbound nitrazepam (intrinsic clearance). Mean values (ranges) were 63 (50-87) ml/min and 489 (377-635) ml/min in the young and 64 (47-91) ml/min and 456 (348-652) ml/min in the elderly subjects respectively. There were no significant differences in elimination half life, clearance and volume of distribution between patients with alcoholic liver cirrhosis and the total of healthy subjects of both age groups, mean values (ranges) being 31 (21-55) h, 59 (26-85) ml/min and 2.17 (1.57-3.22) l/kg respectively in patients and 31 (19-64) h, 63 (47-91) ml/min and 2.38 (1.44-5.33) l/kg in healthy subjects. The protein unbound fraction of nitrazepam was substantially higher in the patient group: 18.9 (14.8-30.3)% as compared to 13.8 (11.0-15.9)% in the healthy subjects ( < 0.001). Clearance calculated relative to unbound nitrazepam (intrinsic clearance) was significantly lower in the patient group: 320 (163-482) ml/min as compared to healthy subjects, 472 (348-652) ml/min ( < 0.001). The results of this study indicate that nitrazepam action following single dose administration may be more persistent in elderly than in young people; however, steady state levels of total and unbound nitrazepam during nightly intake of the drug will not be affected by age. On the other hand, steady state levels of unbound nitrazepam in patients with liver cirrhosis will generally be about 35% higher than in healthy subjects.
在9名相对年轻的健康受试者（年龄22 - 49岁）、8名健康老年人（年龄67 - 76岁）和12名酒精性肝硬化患者（年龄39 - 66岁）中，研究了年龄和肝硬化对静脉注射硝西泮药代动力学的影响。老年受试者中硝西泮的消除半衰期比年轻受试者长，但差异未达到统计学显著性。平均值（范围）分别为38（26 - 64）小时和26（19 - 31）小时。消除半衰期的增加主要是由于分布容积增加，老年组和年轻组的平均值（范围）分别为2.93（1.96 - 5.33）升/千克和1.89（1.44 - 2.23）升/千克（P<0.05）。老年受试者中硝西泮的蛋白结合率倾向于更高，尽管两个年龄组之间的差异不显著：老年组和年轻组分别为13.9（11.5 - 15.4）%和13.0（11.0 - 15.9）%。年龄对总硝西泮清除率和游离硝西泮清除率（内在清除率）均无影响。年轻受试者的平均值（范围）分别为63（50 - 87）毫升/分钟和489（377 - 635）毫升/分钟，老年受试者分别为64（47 - 91）毫升/分钟和456（348 - 652）毫升/分钟。酒精性肝硬化患者与两个年龄组的健康受试者总数在消除半衰期、清除率和分布容积方面无显著差异，患者组的平均值（范围）分别为31（21 - 55）小时、59（26 - 85）毫升/分钟和2.17（1.57 - 3.22）升/千克，健康受试者分别为31（19 - 64）小时、63（47 - 91）毫升/分钟和2.38（1.44 - 5.33）升/千克。患者组中硝西泮的蛋白结合率显著更高：为18.9（14.8 - 30.3）%，而健康受试者为13.8（11.0 - 15.9）%（P<0.001）。相对于游离硝西泮计算的清除率（内在清除率）在患者组中显著更低：为320（163 - 482）毫升/分钟，而健康受试者为472（348 - 652）毫升/分钟（P<0.001）。本研究结果表明，单次给药后硝西泮的作用在老年人中可能比年轻人更持久；然而，夜间服药期间总硝西泮和游离硝西泮的稳态水平不受年龄影响。另一方面，肝硬化患者中游离硝西泮的稳态水平通常比健康受试者高约35%。
