Jones K M, Liao E, Hohneker K, Turpin S, Henry M M, Selinger K, Hsyu P H, Boucher R C, Knowles M R, Dukes G E
Department of Pharmacy Practice, School of Pharmacy, Campbell University, Buies Creek, NC 27506, USA.
Pharmacotherapy. 1997 Mar-Apr;17(2):263-70.
To compare the pharmacokinetics and systemic exposure of nebulized and oral amiloride in adolescents and adults with mild to moderate cystic fibrosis (CF).
Open-label, randomized, two-way crossover, single-dose pharmacokinetic study.
University hospital clinical research unit.
Nine adolescents and 10 adults with mild to moderate CF (forced expiratory volume in 1 sec > or = 50% predicted, Brasfield score > or = 15).
Patients received amiloride solution orally (10 mg of amiloride 1-mg/ml solution) and by inhalation [4.5 ml amiloride of 1-mg/ml solution in 12% saline (approximately 3.8 mmol/L) by DeVilbiss 646 nebulizer] during two study phases separated by a 7- to 28-day washout period. Serial blood and urine samples were collected for 48 and 72 hours, respectively.
After oral dosing, the mean +/- SD maximum peak concentration (Cmax) was 20.6 +/- 10.0 ng/ml at 3.2 +/- 1.2 hours in adults and 21.7 +/- 4.88 at 2.9 +/- 0.6 hours in the adolescents. Mean area under the concentration-time curve (AUC) from time zero to infinity hours was 275 +/- 115 and 254 +/- 60 ng.hr/ml in the adult and adolescent groups; half-life was 16.0 +/- 0.7 and 13.4 +/- 1.4 hours, respectively. After nebulization, 14 of 19 subjects exhibited two concentration peaks (Cmax1 and Cmax2) with mean values of 1.57 +/- 1.67 ng/ml at 0.5 +/- 0.2 hours and 1.37 +/- 1.21 ng/ml at 4.0 +/- 1.0 hours for adults, and 1.49 +/- 0.99 ng/ml at 0.5 +/- 0.1 hours and 1.52 +/- 0.81 ng/ml at 3.3 +/- 0.5 hours for adolescents. Estimated mean +/- SD dose nebulized was 1.91 +/- 0.66 and 2.28 +/- 0.30 mg in the adult and adolescent groups, respectively. Mean +/- SD AUC from time zero to the last measurable plasma amiloride concentration after inhalation was 14.4 +/- 17.6 and 15.4 +/- 10.1 ng.hr/ml in the adults and adolescents. No significant adverse events occurred during the study. Pharmacokinetic parameters were not statistically different between the adolescent and adult groups by route of administration. However significant differences in peak amiloride concentration, AUC, and urinary amiloride excretion were evident when comparing oral versus inhalation administration within each group.
Mean amiloride plasma concentration peaks and AUC after inhalation were significantly lower than after oral dosing. In addition, the second amiloride plasma concentration peak may be due to oral ingestion of the nebulized amiloride, whereas the earlier Cmax1 after inhalation may be due to pulmonary absorption of amiloride. These results suggest that single-dose amiloride inhalation in patients with mild to moderate CF results in minimal systemic exposure compared with oral dosing, and that drug disposition is similar in adolescents and adults with CF.
比较雾化吸入与口服阿米洛利在轻至中度囊性纤维化（CF）青少年和成人中的药代动力学及全身暴露情况。
开放标签、随机、双向交叉、单剂量药代动力学研究。
大学医院临床研究单位。
9名青少年和10名轻至中度CF患者（第1秒用力呼气量≥预测值的50%，布拉斯菲尔德评分≥15）。
在两个研究阶段，患者分别口服阿米洛利溶液（10 mg阿米洛利1 mg/ml溶液）和雾化吸入[使用德维比斯646雾化器将4.5 ml 1 mg/ml阿米洛利溶液加入12%盐水（约3.8 mmol/L）中]，两个阶段之间有7至28天的洗脱期。分别在48小时和72小时采集系列血样和尿样。
口服给药后，成人在3.2±1.2小时的平均±标准差最大峰浓度（Cmax）为20.6±10.0 ng/ml，青少年在2.9±0.6小时为21.7±4.88 ng/ml。成人组和青少年组从零时间到无穷大小时的平均浓度-时间曲线下面积（AUC）分别为275±115和254±60 ng·hr/ml；半衰期分别为16.0±0.7和13.4±1.4小时。雾化吸入后，19名受试者中有14名出现两个浓度峰（Cmax1和Cmax2），成人在0.5±0.2小时的平均值为1.57±1.67 ng/ml，在4.0±1.0小时为1.37±1.21 ng/ml，青少年在0.5±0.1小时为1.49±0.99 ng/ml，在3.3±0.5小时为1.52±0.81 ng/ml。成人组和青少年组雾化吸入的估计平均±标准差剂量分别为1.91±0.66和2.28±0.30 mg。成人和青少年吸入后从零时间到最后可测血浆阿米洛利浓度的平均±标准差AUC分别为14.4±17.6和15.4±10.1 ng·hr/ml。研究期间未发生显著不良事件。按给药途径，青少年组和成人组的药代动力学参数无统计学差异。然而，在每组内比较口服与吸入给药时，阿米洛利峰浓度、AUC和尿中阿米洛利排泄存在显著差异。
吸入后阿米洛利的平均血浆浓度峰和AUC显著低于口服给药后。此外，第二个阿米洛利血浆浓度峰可能是由于雾化吸入的阿米洛利经口摄入，而吸入后较早出现的Cmax1可能是由于阿米洛利的肺部吸收。这些结果表明，轻至中度CF患者单剂量雾化吸入阿米洛利与口服给药相比，全身暴露最小，且CF青少年和成人的药物处置相似。
