THE INFLUENCE OF DRUG INPUT RATE ON THE DEVELOPMENT OF TOLERANCE TO FRUSEMIDE

Aims Understanding the impact of drug input rate on its pharmacokineti c-pharmacodynamic 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 givi ng the drug at four different infusion rates. Methods Eight healthy vo lunteers 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 in fusion rates systematically influenced the frusemide excretion rate ve rsus diuretic and natriuretic response relationship. Counter-clockwise hysteresis occurred for the most rapid infusion rate, whereas a progr essive clockwise hysteresis was observed for the slower infusions, ind icating development of tolerance. For each subject, diuresis and natri uresis were modeled for all four treatments simultaneously, using a fe edback tolerance model. It was not possible to describe the data using a model without tolerance. The time course of tolerance development s howed remarkable differences between the infusion rates. The intensity of maximum tolerance development was significantly less for the slowe st infusion rate compared with the more rapid infusions and it appeare d significantly later. However, no differences in diuretic or natriure tic response were found between the treatments. Conclusions The direct ion 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 tolera nce, is influenced by the drug input rate.