Stockigt J R, Lim C F, Barlow J W, Wynne K N, Mohr V S, Topliss D J, Hamblin P S, Sabto J
J Clin Endocrinol Metab. 1985 May;60(5):1025-31. doi: 10.1210/jcem-60-5-1025.
The diuretic furosemide inhibits serum protein binding of T4 in equilibrium dialysis, dextran-charcoal, and competitive ligand binding separation systems and displaces [125I]T4 from isolated preparations of T4-binding globulin (TBG), prealbumin, and albumin. Equilibrium dialysis studies of undiluted normal serum showed that about 10 micrograms/ml furosemide increased the free T4 and free T3 fractions. Displacement occurred at lower drug concentrations in sera with subnormal albumin and TBG levels. Binding of [14C]furosemide to TBG was inhibited by unlabeled T4, suggesting that furosemide and T4 share a common binding site. A single oral dose of 500 mg furosemide given to five patients maintained on peritoneal dialysis increased the percentage of charcoal uptake of [125I]T4 (using serum diluted 1:10) from 4.1 +/- 1.0 (+/- SE) to 10.8 +/- 4.3 (P less than 0.01) after 2 h, while decreasing total T3 from 75 +/- 5 to 56 +/- 13 ng/dl (P less than 0.01) and total T4 from 6.7 +/- 0.9 to 4.8 +/- 0.8 micrograms/dl (P less than 0.01) after 5 h. Various ligands inhibited [125I]T4 binding to serum proteins in the following relative molar relationship: T4, 1; furosemide, 1.5 X 10(3); fenclofenac, 2 X 10(4); mefenamic acid. 2.5 X 10(4); diphenylhydantoin, 4 X 10[4); ethacrynic acid, 10(5); heparin 5 X 10(5); 2-hydroxybenzoylglycine, 10(6); and sodium salicylate, 1.5 X 10(6). These studies demonstrate that furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower total T4 and T3 levels. The drug is much more potent on a molar basis than other drug inhibitors of T4 binding, but at normal therapeutic concentrations, furosemide is unlikely to decrease serum T4 or T3. However, high doses, diminished renal clearance, hypoalbuminemia, and low TBG accentuate its T4- and T3-lowering effect. Hence, furosemide should be considered a possible cause of low thyroid hormone levels in patients with critical illness. The significance of this drug in reports of impaired hormone and drug binding in renal failure requires further assessment.
在平衡透析、葡聚糖-活性炭和竞争性配体结合分离系统中，利尿剂速尿抑制血清中T4与蛋白质的结合，并从分离的甲状腺素结合球蛋白（TBG）、前白蛋白和白蛋白制剂中置换出[125I]T4。对未稀释的正常血清进行的平衡透析研究表明，约10微克/毫升的速尿可增加游离T4和游离T3的比例。在白蛋白和TBG水平低于正常的血清中，较低的药物浓度即可发生置换。未标记的T4可抑制[14C]速尿与TBG的结合，提示速尿和T4共用一个结合位点。给5例维持腹膜透析的患者单次口服500毫克速尿后，2小时时[125I]T4的活性炭摄取百分比（使用1:10稀释的血清）从4.1±1.0（±标准误）增至10.8±4.3（P<0.01），而5小时时总T3从75±5降至56±13纳克/分升（P<0.01），总T4从6.7±0.9降至4.8±0.8微克/分升（P<0.01）。各种配体对[125I]T4与血清蛋白结合的抑制作用呈以下相对摩尔关系：T4为1；速尿为1.5×10³；芬氯酸为2×10⁴；甲灭酸为2.5×10⁴；苯妥英为4×10⁴；依他尼酸为10⁵；肝素为5×10⁵；2-羟基苯甲酰甘氨酸为10⁶；水杨酸钠为1.5×10⁶。这些研究表明，速尿可竞争TBG、前白蛋白和白蛋白上的T4结合位点，因此单次高剂量可急性降低总T4和T3水平。按摩尔计算，该药比其他T4结合抑制剂更有效，但在正常治疗浓度下，速尿不太可能降低血清T4或T3。然而，高剂量、肾清除率降低、低白蛋白血症和低TBG会增强其降低T4和T3的作用。因此，速尿应被视为危重病患者甲状腺激素水平降低的一个可能原因。该药在肾衰竭时激素与药物结合受损报告中的意义需要进一步评估。
