A study of the pharmacodynamic differences between immediate and extended release bumetanide formulations

Abstract

Optimized bumetanide extended (ER) and immediate release (IR) formulations were developed using fluid bed layering and coating techniques. We postulated that the ER bumetanide formulation would have more effective and sustained diuretic and saluretic effects than IR. The diuretic/saluretic effects of both formulations were measured in rabbits ( n=8) for two days after dosing with 1 mg/kg bumetanide. During the first day, both formulations produced 2–3 times more urine volume and sodium excretion than baseline. In the first 24 h, despite less bumetanide excretion from the ER formulation (101±13.9 μg/kg compared to 146±14.6 μg/kg for the IR formulation; P<0.04); the ER formulation produced diuresis and natriuresis that was equivalent to that of the IR formulation. In contrast, urine production in the IR formulation group fell below that of placebo controls on day 2. During the second day, the ER formulation was noted to produce persistent bumetanide excretion; the diuretic and natriuretic effects were not statistically significant from baseline control. We speculate that the decrease in response to bumetanide observed especially for the IR formulation during the second day may be due to the activation of compensatory counter-regulatory homeostatic mechanism(s). We conclude that the ER formulation had similar diuretic/saluretic effects but better drug excretion to urine production efficiencies than the IR formulation in the healthy rabbit model. The ER formulation, while providing comparable diuretic/saluretic effect to the IR formulation, offers the advantage of avoiding the initial, rapid and robust diuretic effect experienced with the IR formulations. Taken together, the data provide sufficient basis to warrant further investigation and refinement of our ER bumetanide formulation in humans.