PHARMACODYNAMIC MODELING OF FUROSEMIDE TOLERANCE AFTER MULTIPLE INTRAVENOUS ADMINISTRATION

Citation
M. Wakelkamp et al., PHARMACODYNAMIC MODELING OF FUROSEMIDE TOLERANCE AFTER MULTIPLE INTRAVENOUS ADMINISTRATION, Clinical pharmacology and therapeutics, 60(1), 1996, pp. 75-88
Citations number
29
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
0009-9236
Volume
60
Issue
1
Year of publication
1996
Pages
75 - 88
Database
ISI
SICI code
0009-9236(1996)60:1<75:PMOFTA>2.0.ZU;2-F
Abstract
Objective: Physiologic indirect-response models have been proposed to account for the pharmacodynamics of drugs with an indirect mechanism o f action, such as furosemide. However, they have not been applied to t olerance development, The aim of this study was to investigate the dev elopment of tolerance after multiple intravenous dosing of furosemide in healthy volunteers, Methods: Three repetitive doses of 30 mg furose mide were given as rapid intravenous infusions at 0, 4, and 8 hours to eight healthy volunteers, Urine samples were collected for a period u p to 14 hours after the first dose, Volume and sodium losses were isov olumetrically replaced with an oral rehydration fluid, Results: Tolera nce was demonstrated as a significant decrease in diuretic and natriur etic response over time, Total mean diuresis was 35% lower (P < 0.01) and total mean natriuresis was 52% lower (p < 0.0001) after the third dose of furosemide compared with the first dose, However, there were c onsiderable interindividual variations in the rate and extent of toler ance development for both diuresis and natriuresis, Pharmacokinetic-ph armacodynamic modeling of tolerance development was performed with use of an indirect-response model with an additional ''modifier'' compart ment, This model gave an accurate description of the diuretic and natr iuretic data after multiple dosing of furosemide and enabled the estim ation of a lag-time for tolerance and a rate constant for tolerance de velopment, Physiologic counteraction was demonstrated as a significant increase in plasma active renin levels (p < 0,00001) and a decrease i n atrial natriuretic peptide levels (P < 0.005) during the day, concom itantly with the development of a negative sodium balance, This may be viewed as physiologic reflections of the modifier in our model, Concl usion: Indirect-response models may be successfully applied for tolera nce modeling of drugs after multiple dosing.