Development of acute tolerance to bumetanide: bolus injection studies

Bumetanide was administered intravenously to four mongrel dogs, in a random crossover fashion, at doses of 0.05 mg/kg (I), 0.15 mg/kg (II), and 0.5 mg/kg (III) where urinary losses were replaced with lactated Ringer's solution at 1.5 ml/min (hydropenic conditions) or at a dose of 0.5 mg/kg (IV) where urinary losses were replaced with lactated Ringer's solution isovolumetrically (euvolemic conditions). Serial plasma and urine samples were assayed for bumetanide by high-performance liquid chromatography (HPLC) and for sodium by flame photometry. There were no significant differences in the pharmacokinetic parameters of bumetanide among Treatments I-IV. The dynamic parameters Emax (maximum effect attributable to the drug) and s (slope factor) were not different between treatments. However, a consistent, demonstrable increase in ER50 (urinary excretion rate of drug producing 50% of Emax) was observed among Treatments I (2.34 micrograms/min), II (3.92 micrograms/min), and III (6.54 micrograms/min); also, a significant decrease in ER50 was observed between Treatment III (6.54 micrograms/min) and Treatment IV (2.66 micrograms/min). These results show that hydration status has a marked effect on natriuretic and diuretic response and that tolerance can rapidly develop within a single intravenous dose of bumetanide.