The influence of food intake on the effect of two controlled release formulations of furosemide

Abstract

Differences in the urinary excretion rate of furosemide may explain discrepancies observed between the bioavailability and the total diuretic effect of different formulations of this drug. Furosemide was given at a dose of 60 mg as two oral controlled release (CR) formulations (FR and LR), with and without breakfast, in a randomized, four-treatment, four-period, crossover design to 28 healthy volunteers. Urinary volume, and contents of furosemide and sodium, were measured in samples taken over 24 h. The extent and rate of absorption of furosemide from FR were decreased after breakfast as compared to fasting: the mean (SD) of total furosemide excreted decreased from 11.38 (3.12) to 7.73 (1.67) mg, p < 0.0001, and the median (range) mean residence time increased from 6.3 (4.1-9.3) to 9.5 (5.9-11.8) h, p < 0.001. On the other hand, the extent of absorption of LR was increased after breakfast, from 8.04 (3.32) to 9.45 (1.83) mg, p < 0.05, without a significant change in MRT. FR had a higher extent and rate of absorption than LR during fasting, but its extent of absorption was lower than that of LR in the postprandial state. Interestingly, the total fraction of furosemide absorbed, as estimated from total furosemide excretion, was not correlated with the total diuresis (r2 = 0.079) and the differences in drug response compared among the four periods were much smaller than would be expected from the differences in amount absorbed. This discrepancy may be explained by differences in urinary excretion rate of furosemide and, related to this, differences in efficiency profiles between the four treatments. Therefore, the urinary excretion profile of a formulation of furosemide may be more important for the cumulated drug effect than the amount absorbed.

The influence of drug input rate on the development of tolerance to frusemide

“…For the loop diuretic frusemide, it has been shown that if identical total doses are given, a slow and constant input of the drug into the body induces a higher total effect compared with a rapid administration. This has been explained by investigating the efficiency of the drug [ 3–9]. However, the pharmacokinetic‐pharmacodynamic relationship of frusemide may be altered by development of tolerance [ 6, 9, 10].…”

“…The rapid intravenous administration of multiple frusemide doses activates counter‐regulatory mechanisms leading to a profound decrease in diuretic and natriuretic effects [ 12]. However, clockwise hysteresis, (a sign of tolerance development) has been observed during slow input of the drug, for example after the administration of oral doses of frusemide in combination with food or of controlled release formulations [ 5, 7, 10]. Understanding the consequences of changing drug input rate for its pharmacokinetic‐pharmacodynamic profile may lead to more adequate drug therapy.…”

Clinical Consequences of the Biphasic Elimination Kinetics for the Diuretic Effect of Furosemide and its Acyl Glucuronide in Humans

“…During the diuresis, 2260 AE 755 mL was excreted above the base line value of 1 mL min À1 for the unmedicated and well-hydrated subjects (Paintaud et al 1995;Vree et al 1995b;Dormans et al 1996). Despite the fact that the subjects maintained their normal drinking and eating patterns, during and after this excess urine excretion period, it took three days for the body to regain this amount of¯uid.…”

“…By inhibiting the tubular reabsorption of Cl À and Na ions, furosemide increases the net urine¯ow or urine production rate per minute Duchin et al 1977;Hammarlund et al 1984). This effect can be related to the plasma con-centration±time curve, or to the renal excretion rate (Hammarlund-Udenaes & Benet 1989;Sjo Èstro Èm et al 1989;Alva Ân et al 1992;Paintaud et al 1995;Yagi et al 1996;Murray et al 1997). The constructed concentration-effect (urine¯ow, sodium excretion rate) curves of furosemide for the descending part of the elimination curves of the plasma concentrations and renal excretion rates run nearly parallel.…”

Food: An Unrecognized Source of Loop Diuretic Resistance

“…These drugs are highly protein bound in the blood and do not enter the tubular lumen through glomerular filtration; they are secreted from the blood into the urine through the organic acid transport pathway in the straight segment of the proximal tubule. 1 The transport pathway avidly secretes all loop diuretics and is relatively independent of the flow to the tubule. Only other organic acids, such as probenecid, alter loop diuretic secretion by competing for transport in the proximal tubule.…”