Bioavailability and Diuretic Effect after Administration of Retarded Capsules of Bumetanide in Human Subjects.

Abstract

Retarded capsules containing 1 mg bumetanide (BN) were prepared and their in vivo absorption and diuretic effect after oral administration in human subjects were studied. For comparison, commercially available tablets of BN (rapid effect) were administered orally. The mean value of the area under the plasma concentration time curve (AUC) after administration of retarded capsules was about one half that of the tablets. The mean maximum plasma concentration (Cmax) and the mean maximum urinary excretion rate of BN after administration of retarded capsules were also about one half compared to those of the tablets. Cumulative urinary volumes for 24 h, however, were not significantly different between retarded capsules and tablets. Peak times for the urinary excretion rate of BN, urine flow rate and the Cmax after administration of retarded capsules were significantly delayed compared to those of tablets. Clockwise hysteresis relationships between the urine flow rate and plasma concentration or urinary excretion rate of BN were observed after administration of retarded capsules. From these studies, retarded capsules of BN possessed a mild diuresis and its diuretic effect was maintained for a few hours after administration.

Understanding the Hysteresis Loop Conundrum in Pharmacokinetic / Pharmacodynamic Relationships

“…However, in the case of the bumetanide retarded capsules a clockwise hysteresis was evident in the relationship between urinary excretion rate and urine flow rate. In this case the urine flow rate maximum was achieved before the plasma C max or maximum of urinary excretion in the case of bumetanide [20]. Similar results were obtained with furosemide (another loop diuretic) for which minimal counter-clockwise hysteresis was observed for plain tablets (Furix®) while controlled release formulations (Furix Retard® and Lasix Retard®) exhibited clear clockwise hysteresis when the diuretic effect versus furosemide excretion rate were correlated [38].…”

“…For instance, bumetanide as a tablet exhibited counter-clockwise hysteresis because a time lag between plasma concentration and diuretic effect is evident since the drug acts directly in the renal tubule or because of variations in absorption rate from the GI tract. However, in the case of the retarded capsules a clockwise hysteresis was present because the maximum urine flow rate was achieved before the plasma C max or before the maximum of urinary excretion [20]. Thus, it can be clearly observed that the pharmaceutical formulation may change the pharmacodynamics of a drug.…”

“…Thus, by altering the formulation in which a drug is prepared and thereby altering its input rate may also affect the direction of the hysteresis loop at various steps in the process (Figures 2 and 3). For instance, the loop diuretic bumetanide (1 mg) was administered orally to healthy subjects as tablets and as retarded capsules (containing sustained release granules) [20]. In the case of the tablet formulation a counter-clockwise hysteresis was present and it was determined that this was caused due to the time lag between plasma concentration and diuretic effect because bumetanide acts directly in the renal tubule or because of variations in absorption rate from the GI tract [20].…”

“…For instance, the loop diuretic bumetanide (1 mg) was administered orally to healthy subjects as tablets and as retarded capsules (containing sustained release granules) [20]. In the case of the tablet formulation a counter-clockwise hysteresis was present and it was determined that this was caused due to the time lag between plasma concentration and diuretic effect because bumetanide acts directly in the renal tubule or because of variations in absorption rate from the GI tract [20]. However, in the case of the bumetanide retarded capsules a clockwise hysteresis was evident in the relationship between urinary excretion rate and urine flow rate.…”