Branch R A, Roberts C J, Homeida M, Levine D
Br J Clin Pharmacol. 1977 Apr;4(2):121-7. doi: 10.1111/j.1365-2125.1977.tb00682.x.
The pharmacokinetic and diuretic response of frusemide have been investigated in six normal subjects. Frusemide (80 mg) was administered (a) intravenously to unstressed subjects, (b) orally to unstressed subjects, (c) orally to sodium depleted subjects who had received 80 mg oral frusemide 36 h previously followed by a 20 mmol sodium, 160 mmol potassium diet. After i.v. administration, the logarithmic plasma concentration-time curve was biexponential. There was a linear relationship between the frusemide plasma concentration in the β-phase of elimination and the rate of sodium excretion. Urinary clearance of frusemide was 60% of total plasma clearance, similarly recovery of frusemide in the urine over 36 h was 65% of the dose administered. These observations suggested an extrarenal route of elimination. After oral administration there was also a linear relationship between frusemide plasma concentration and rate of sodium excretion. Oral bioavailability estimated from the ratio of the areas under the plasma concentration-time curve (AUC) and urine recovery over 36 h after i.v. and oral administration was approximately 50%, yet the diuretic response was similar. The AUC of the β-phase after i.v. administration was similar to the total AUC after oral administration suggesting that response was related to drug present in a tissue pool rather than in plasma. After sodium depletion, there was no change in frusemide kinetics, however the diuretic response decreased. Once again, there was a significant relationship between plasma concentration and rate of sodium excretion. This relationship during the elimination phase after oral administration to sodium depleted subjects was significantly shifted to the right compared to the elimination phase after oral administration to unstressed subjects, suggesting a change in plasma concentration response. In conclusion, the response to frusemide is determined by the concentration of drug in the tissue comparement. This response is modified by factors controlling sodium homeostasis.
已在6名正常受试者中研究了速尿的药代动力学和利尿反应。速尿（80毫克）通过以下方式给药：(a) 静脉注射给未应激的受试者；(b) 口服给未应激的受试者；(c) 口服给钠缺乏的受试者，这些受试者在36小时前已口服80毫克速尿，随后采用20毫摩尔钠、160毫摩尔钾的饮食。静脉注射给药后，对数血浆浓度-时间曲线呈双指数。在消除的β期，速尿血浆浓度与钠排泄率之间存在线性关系。速尿的尿清除率为总血浆清除率的60%，同样，36小时内尿中速尿的回收率为给药剂量的65%。这些观察结果提示存在肾外消除途径。口服给药后，速尿血浆浓度与钠排泄率之间也存在线性关系。根据静脉注射和口服给药后血浆浓度-时间曲线下面积（AUC）之比以及36小时内尿回收率估算的口服生物利用度约为50%，但利尿反应相似。静脉注射给药后β期的AUC与口服给药后的总AUC相似，表明反应与组织池中的药物有关，而非与血浆中的药物有关。钠缺乏后，速尿动力学无变化，但利尿反应降低。同样，血浆浓度与钠排泄率之间存在显著关系。与给未应激受试者口服给药后的消除期相比，给钠缺乏受试者口服给药后消除期的这种关系明显右移，提示血浆浓度反应发生了变化。总之，对速尿的反应取决于组织隔室中药物的浓度。这种反应受控制钠稳态的因素调节。
