Kinetics, dynamics, and bioavailability of bumetanide in healthy subjects and patients with congestive heart failure

Abstract

Four healthy subjects and six patients with congestive heart failure (CHF) were given 3 mg oral and intravenous doses of bumetanide in a random crossover fashion. Bumetanide was analyzed by HPLC, and sodium and potassium was analyzed by flame photometry. Aside from a modest reduction in renal clearance, the kinetics of bumetanide in CHF were similar to those in healthy subjects. The extent of bioavailability was 81%, with a variability of 20% to 25% about the mean for both groups. The cumulative dynamic responses to bumetanide, whether administered orally or intravenously, were essentially the same in each group. Pharmacodynamic modeling showed that there were no significant differences between healthy subjects and patients with CHF in either ER50 (bumetanide urinary excretion rate producing 50% of maximum drug effect) or S (slope), although the baseline effect was 15 times lower in CHF. The maximum effect attributable to bumetanide was twofold higher in healthy subjects and there was a significant correlation between this parameter and creatinine clearance (r = 0.964; p less than 0.001). Overall, these results indicate that a predictable transition from 3 mg intravenous to oral doses of bumetanide is possible in CHF.

The Pharmacokinetics of Bumetanide in the Newborn Infant

“…The mean renal clearance was lower in neonates receiving 0.05 mg/kg bumetanide. Overall, the renal clearance of bumetanide (range 0.02-0.35 ml/min/kg in our study) was 10% of previously reported adult values and is comparable to values reported in the litera ture for the neonate [2,3,[5][6][7][8]14]. Creati nine clearances in our study (range 0.18-1.12 ml/min-kg) were consistent with other reported values (approximately 30% of healthy adult values) [4], In adults, renal ex cretion of bumetanide occurs via glomerular filtration and tubular secretion.…”

“…The weight-normalized serum clearance of bumetanide (range 0.2-1.0 ml/min/kg in neo nates in our study) was approximately 20% of previously reported adult plasma clearance values and is comparable to previously re ported values in premature and term neonates [2,3,[5][6][7][8]14]. The steady-state volume of dis tribution (0.15-0.32 1/kg in our study) was found to be equal to or twice the previously reported adult values [2,3].…”

The renin angiotensin aldosterone system and frusemide response in congestive heart failure.

“…Despite the proven efficacy of loop diuretics in patients with CHF, supranormal doses are typically required in order to achieve a natriuretic response [6][7][8][9]. The cause for resistance to these drugs is unknown.…”

“…The cause for resistance to these drugs is unknown. Prior studies have essentially excluded a pharmacokinetic cause [6][7][8][9]. Thus, some undefined pharmacodynamic abnormality is presumed culpable.…”

Effects of water deprivation on drug pharmacokinetics: Correlation between drug metabolism and hepatic CYP isozymes

“…Unexpectedly, 48-h dehydration slowed (by 41.2%) the Cl nr of bumetanide after 8-mg/kg bumetanide (intravenously) in male SD rats (Huang et al, 1993). In humans, bumetanide is excreted mainly in the urine (60 ± 20% of the dose) as an unchanged diuretic (Cook et al, 1988), whereas only 10% of the dose is excreted in the urine of rats (Choi et al, 1991b;Huang et al, 1993).…”