Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers
Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers
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DOI：
10.1097/ftd.0b013e3181816214
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发表时间：
2008-08-01
影响因子：
2.5
通讯作者：
Graudins, Andis
中科院分区：
文献类型：
--
作者：
Dowling, Jonathonm;Isbister, Geoffrey K.;Graudins, Andis
为了研究纳洛酮在健康志愿者中的药代动力学，我们进行了一项开放标签交叉研究，其中6名男性志愿者在5种情况下接受纳洛酮：静脉注射（0.8 mg）、肌肉注射（0.8 mg）、鼻内注射（0.8 mg）、静脉注射（2 mg）和鼻内注射（2 mg）。给药后4小时采集样本，共128份。使用NONMEM进行群体药代动力学分析。数据最好用三室模型来描述，其中肌肉和鼻内给药的一级吸收，受试者之间清除率和中心容积的变异性，清除率的瘦体重和中心容积的体重。肌内纳洛酮和鼻内纳洛酮的相对生物利用度分别为36%和4%。最终参数估计为间隙91 L/hr；中心容积2.87 L；第一外周室容积1.49 L，第二外周室容积33.6 L；第一次室间间隙5.66 L/hr；第二次室间间隙29.8 L/hr；Ka（肌内），0.65；Ka（鼻内），1.52。肌内纳洛酮达到浓度峰值的中位时间为12分钟，鼻内纳洛酮为6至9分钟。静脉注射和肌肉注射纳洛酮可立即提供高浓度，然后持续4小时可检测到浓度。鼻内纳洛酮的生物利用度较肌内低。静脉和肌肉联合给药可能是纳洛酮输注的有效替代方法。
To investigate the pharmacokinetics of naloxone in healthy volunteers, we undertook an open-label crossover study in which six male volunteers received naloxone on five occasions: intravenous (0.8 mg), intramuscular (0.8 mg), intranasal (0.8 mg), intravenous (2 mg), and intranasal (2 mg). Samples were collected for 4 hours after administration for 128 samples in total. A population pharmacokinetic analysis was undertaken using NONMEM. The data were best described by a three-compartment model with first-order absorption for intramuscular and intranasal administration, between-subject variability on clearance and central volume, lean body weight on clearance, and weight on central volume. Relative bioavailability of intramuscular and intranasal naloxone was 36% and 4%, respectively. The final parameter estimates were clearance, 91 L/hr; central volume, 2.87 L; first peripheral compartment volume, 1.49 L, second peripheral compartment volume, 33.6 L; first intercompartmental clearance, 5.66 L/hr; second intercompartmental clearance, 29.8 L/hr; Ka (intramuscular), 0.65; and Ka (intranasal), 1.52. Median time to peak concentration for intramuscular naloxone was 12 minutes and for intranasal, 6 to 9 minutes. A combination of intravenous and intramuscular naloxone provided immediate high and then detectable concentrations for 4 hours. Intranasal naloxone had poor bioavailability compared with intramuscular. Combined intravenous and intramuscular administration may be a useful alternative to naloxone infusions.