Pharmacodynamic modeling of furosemide tolerance after multiple intravenous administration

摘要: Objective Physiologic indirect-response models have been proposed to account for the pharmacodynamics of drugs with an indirect mechanism action, such as furosemide. However, they not applied tolerance development. The aim this study was investigate development after multiple intravenous dosing furosemide in healthy volunteers. Methods Three repetitive doses 30 mg were given rapid infusions at 0, 4, and 8 hours eight volunteers. Urine samples collected a period up 14 first dose. Volume sodium losses isovolumetrically replaced oral rehydration fluid. Results Tolerance demonstrated significant decrease diuretic natriuretic response over time. Total mean diuresis 35% lower (p < 0.01) total natriuresis 52% 0.0001) third dose compared there considerable interindividual variations rate extent both natriuresis. Pharmacokinetic-pharmacodynamic modeling performed use model additional “modifier” compartment. This gave accurate description data enabled estimation lag-time constant Physiologic counteraction increase plasma active renin levels 0.00001) atrial peptide 0.005) during day, concomitantly negative balance. may be viewed physiologic reflections modifier our model. Conclusion Indirect-response successfully dosing. Clinical Pharmacology & Therapeutics (1996) 60, 75–88; doi: