Murray M D, Haag K M, Black P K, Hall S D, Brater D C
Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.
Pharmacotherapy. 1997 Jan-Feb;17(1):98-106.
To determine the between- and within-patient variability of furosemide bioavailability and natriuretic response, and whether four marketed products differ in bioavailability and response.
Open-label, crossover study.
General clinical research center at an academic medical center.
Convenience sample of 17 patients age 65 +/- 6 years receiving diuretics for the treatment of hypertension or congestive heart failure.
Each patient received each of five furosemide products (one intravenous and four oral tablet formulations) twice in random order for a total of 10 treatments.
Measurements included absolute bioavailability using cumulative amounts of urinary furosemide collected over 8 hours after oral versus intravenous dosing, and cumulative amounts of urinary sodium. Extensive between- and within-patient variability in all measured values rendered any differences among the products neither clinically nor statistically significant. Mean (+/-SD) bioavailability was 49 +/- 17% (range 12-112%) and coefficients of variation with different products were from 25-43%. Coefficients of variation for urinary furosemide excretion and urinary sodium excretion were also large, 25-42% and 23-51%, respectively. Multivariate analyses that incorporated between- and within-patient effects failed to reveal differences among the products for bioavailability (F = 1.04, p = 0.403), urinary furosemide excretion (F = 1.09, p = 0.371), or urinary sodium excretion (F = 0.97, p = 0.448). Correlation coefficients were 0.81-0.85 for the rates of sodium and furosemide excretion, and half-maximum response using a sigmoid Emax model did not differ among products.
Although furosemide concentration in urinary and natriuretic responses showed good correlation, variability in bioavailability considerably affects the drug's excretion into urine. Variability in absorption both among patients and within an individual patient is great and overwhelms any differences in bioavailability among approved furosemide products. Switching from one formulation to another will not likely result in any predictable change in patient response.
确定呋塞米生物利用度和利钠反应在患者之间及患者自身的变异性，以及四种市售产品在生物利用度和反应方面是否存在差异。
开放标签、交叉研究。
一所学术医疗中心的综合临床研究中心。
方便抽样选取17例年龄为65±6岁、因高血压或充血性心力衰竭接受利尿剂治疗的患者。
每位患者以随机顺序接受五种呋塞米产品（一种静脉注射剂和四种口服片剂）中的每一种各两次，共进行10次治疗。
测量指标包括口服与静脉给药后8小时收集的尿呋塞米累积量计算的绝对生物利用度，以及尿钠累积量。所有测量值在患者之间及患者自身均存在广泛变异性，使得各产品之间的任何差异在临床和统计学上均无显著性。平均（±标准差）生物利用度为49±17%（范围12 - 112%），不同产品的变异系数为25% - 43%。尿呋塞米排泄和尿钠排泄的变异系数也很大，分别为25% - 42%和23% - 51%。纳入患者之间及患者自身效应的多变量分析未能揭示各产品在生物利用度（F = 1.04，p = 0.403）、尿呋塞米排泄（F = 1.09，p = 0.371）或尿钠排泄（F = 0.97，p = 0.448）方面存在差异。钠和呋塞米排泄率的相关系数为0.81 - 0.85，使用S形Emax模型的半数最大反应在各产品之间无差异。
尽管尿中呋塞米浓度与利钠反应显示出良好的相关性，但生物利用度的变异性极大地影响了药物向尿液中的排泄。患者之间以及个体患者自身的吸收变异性很大，掩盖了已批准的呋塞米产品之间生物利用度的任何差异。从一种剂型转换为另一种剂型不太可能导致患者反应出现任何可预测的变化。
