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

Abstract

Aims Understanding the impact of drug input rate on its pharmacokineticpharmacodynamic relationship may lead to a more optimal drug therapy. The aim of the present study was to investigate the influence of the rate of administration on tolerance development to frusemide, by giving the drug at four different infusion rates. Methods Eight healthy volunteers were given 10 mg of frusemide on four different occasions, as a constant-rate intravenous infusion during 10, 30, 100 and 300 min, respectively. Urinary volume and contents of frusemide and sodium were measured in samples collected over 8 h. Results The four different infusion rates systematically influenced the frusemide excretion rate versus diuretic and natriuretic response relationship. Counter-clockwise hysteresis occurred for the most rapid infusion rate, whereas a progressive clockwise hysteresis was observed for the slower infusions, indicating development of tolerance. For each subject, diuresis and natriuresis were modeled for all four treatments simultaneously, using a feedback tolerance model. It was not possible to describe the data using a model without tolerance. The time course of tolerance development showed remarkable differences between the infusion rates. The intensity of maximum tolerance development was significantly less for the slowest infusion rate compared with the more rapid infusions and it appeared significantly later. However, no differences in diuretic or natriuretic response were found between the treatments. Conclusions The direction of the hysteresis loop is dependent on the input rate of frusemide. After the administration of a single low dose of frusemide, the time course of tolerance, rather than the integrated time course of tolerance, is influenced by the drug input rate.

Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of torasemide in rabbits

“…The increased diuretic effects with increasing infusion times have also been reported when the same dose of furosemide was infused for 10 s, 30 min, 2 h and 8 h to dogs [7] and bumetanide for 10 s, 1 h and 4 h to rabbits [8]. It has been reported that the direction of the hysteresis loop is dependent on the input rate of furosemide and that the time course of tolerance development to furosemide is influenced by the drug input rate [35]. A slow and constant administration of the drug may lead to a higher diuretic efficiency and delay and blunt the development of tolerance [35].…”

Contribution of the active metabolite, norcocaine, to cocaine's effects after intravenous and oral administration in rats: pharmacodynamics

“…Taken together, the faster onset and greater intensity of the local anesthetic effects produced by IV norcocaine could retard norcocaine's effects on locomotor activity; correspondingly, PO norcocaine produced greater effects on spontaneous activity compared to IV or IP norcocaine. The effects of rate of drug administration on PD have been demonstrated both in humans (Wakelkamp et al 1998) and in rats (Cleton et al 1999;Sun and Lau 2000). For example, acute tolerance to effects of clozapine is route-and dose-dependent, which is closely related to the rate of drug administration .…”

A pharmacokinetic/pharmacodynamic model capturing the time course of torasemide‐induced diuresis in the dog

“…Therefore, the use of tolerance models to describe the pharmacodynamics of torasemide was meaningful. Tolerance phenomenon has already been observed with furosemide in both animals (Hammarlund & Paalzow, ; Li et al ., ; Uechi et al ., ; Hori et al ., ) and humans (Hammarlund et al ., ; Wakelkamp et al ., ; ‐ Wakelkamp et al ., ; Klausner et al ., ). To the best of our knowledge, acute tolerance phenomenon for torasemide in the dog has never been described before.…”

“…a ) , k out was stimulated by the moderator, as proposed for furosemide by Wakelkamp et al . (Wakelkamp et al ., ; Wakelkamp et al ., ). The loss of R is indirectly dependant on M .…”