Sarfez Pharmaceuticals, Inc., McLean, VA.
Division of Cardiology, University of Michigan, Ann Arbor, MI.
J Am Heart Assoc. 2017 Oct 5;6(10):e006135. doi: 10.1161/JAHA.117.006135.
Loop diuretics are highly natriuretic but their short duration of action permits postdiuretic sodium retention, which limits salt loss unless dietary salt is severely restricted. We tested the hypothesis that a more prolonged duration of action would enhance salt loss.
Ten healthy participants were crossed over between 20 mg of oral immediate-release or extended-release (ER) torsemide while consuming a fixed diet with 300 mmol·d of Na. Compared with immediate-release, plasma torsemide after ER was 59% lower at 1 to 3 hours but 97% higher at 8 to 10 hours as a result of a >3-fold prolongation of time to maximal plasma concentrations. The relationship of natriuresis to log torsemide excretion showed marked hysteresis, but participants spent twice as long with effective concentrations of torsemide after ER, thereby enhancing diuretic efficiency. Compared with immediate-release, ER torsemide did not reduce creatinine clearance and increased fluid (1634±385 versus 728±445 mL, <0.02) and Na output (98±15 versus 42±17 mmol, <0.05) despite an 18% reduction in exposure. Neither formulation increased K excretion.
Torsemide ER prolongs urine drug levels, thereby increasing the time spent with effective drug concentrations, reduces postdiuretic Na retention, and moderates a fall in glomerular filtration rate. It caused significant Na loss even during very high salt intake. Thus, a short duration of action limits salt loss with loop diuretics. These conclusions warrant testing in subjects with edema and heart failure.
袢利尿剂具有很强的排钠作用，但由于其作用时间短，会导致利尿后钠潴留，除非严格限制饮食中的盐摄入，否则会限制盐的丢失。我们假设延长作用时间会增强盐的丢失。
10 名健康参与者交叉服用 20mg 口服速释或缓释（ER）托塞米，同时摄入含 300mmol·d 的钠的固定饮食。与速释相比，ER 后托塞米的血浆浓度在 1 至 3 小时降低了 59%，但在 8 至 10 小时增加了 97%，这是由于达到最大血浆浓度的时间延长了>3 倍。利尿作用与托塞米排泄的对数关系显示出明显的滞后，但参与者在 ER 后有效托塞米浓度下的时间延长了一倍，从而提高了利尿效率。与速释相比，ER 托塞米并未降低肌酐清除率，反而增加了液体（1634±385 与 728±445mL，<0.02）和钠排泄量（98±15 与 42±17mmol，<0.05），尽管暴露量减少了 18%。两种制剂均未增加 K 排泄。
托塞米 ER 延长了尿液中的药物水平，从而增加了有效药物浓度的时间，减少了利尿后钠潴留，并适度降低了肾小球滤过率。即使在高盐摄入期间，它也会导致显著的钠丢失。因此，作用时间短限制了袢利尿剂的盐丢失。这些结论值得在水肿和心力衰竭患者中进行测试。
