Wakelkamp M, Alván G, Scheinin H, Gabrielsson J
Department of Medical Laboratory Sciences & Technology, Karolinska Institute, Huddinge University Hospital, Sweden.
Br J Clin Pharmacol. 1998 Nov;46(5):479-87. doi: 10.1046/j.1365-2125.1998.00802.x.
Understanding the impact of drug input rate on its pharmacokinetic-pharmacodynamic relationship may lead to a more optimal drug therapy. The aim of the present study was to investigate the influence of the rate of administration on tolerance development to frusemide, by giving the drug at four different infusion rates.
Eight healthy volunteers were given 10 mg of frusemide on four different occasions, as a constant-rate intravenous infusion during 10, 30, 100 and 300 min, respectively. Urinary volume and contents of frusemide and sodium were measured in samples collected over 8 h.
The four different infusion rates systematically influenced the frusemide excretion rate versus diuretic and natriuretic response relationship. Counter-clockwise hysteresis occurred for the most rapid infusion rate, whereas a progressive clockwise hysteresis was observed for the slower infusions, indicating development of tolerance. For each subject, diuresis and natriuresis were modeled for all four treatments simultaneously, using a feedback tolerance model. It was not possible to describe the data using a model without tolerance. The time course of tolerance development showed remarkable differences between the infusion rates. The intensity of maximum tolerance development was significantly less for the slowest infusion rate compared with the more rapid infusions and it appeared significantly later. However, no differences in diuretic or natriuretic response were found between the treatments.
The direction of the hysteresis loop is dependent on the input rate of frusemide. After the administration of a single low dose of frusemide, the time course of tolerance, rather than the integrated time course of tolerance, is influenced by the drug input rate.
了解药物输入速率对其药代动力学 - 药效学关系的影响可能会带来更优化的药物治疗。本研究的目的是通过以四种不同的输注速率给予呋塞米，来研究给药速率对呋塞米耐受性发展的影响。
八名健康志愿者在四个不同的场合分别接受10毫克呋塞米，分别在10、30、100和300分钟内进行恒速静脉输注。在8小时内收集的样本中测量尿量以及呋塞米和钠的含量。
四种不同的输注速率系统地影响了呋塞米排泄率与利尿和利钠反应之间的关系。最快输注速率出现逆时针滞后，而较慢输注速率则观察到逐渐的顺时针滞后，表明耐受性的发展。对于每个受试者，使用反馈耐受性模型同时对所有四种治疗的利尿和利钠作用进行建模。使用无耐受性的模型无法描述数据。耐受性发展的时间进程在输注速率之间显示出显著差异。与较快输注速率相比，最慢输注速率下最大耐受性发展的强度明显较小，且出现时间明显较晚。然而，各治疗之间在利尿或利钠反应方面未发现差异。
滞后环的方向取决于呋塞米的输入速率。单次给予低剂量呋塞米后，耐受性的时间进程而非耐受性的综合时间进程受药物输入速率的影响。
