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Pharmacokinetics and pharmacodynamics of intravenous trasemide in mutant nagase aalbuminemic rats
Author(s) -
Kim Eun J.,
Lee Myung G.
Publication year - 2003
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.333
Subject(s) - furosemide , diuretic , pharmacokinetics , excretion , chemistry , endocrinology , loop diuretic , urine , pharmacodynamics , medicine , pharmacology
The importance of plasma protein binding of intravenous furosemide in circulating blood for its urinary excretion and hence its diuretic effects in mutant Nagase analbuminemic rats (NARs, an animal model for human familial analbuminemia) was reported. Based on the furosemide report, the diuretic effects of another loop diuretic, torasemide, could be expected in NARs if plasma protein binding of torasemide is considerable in the rats. This was proven by this study. After intravenous administration of torasemide, 10 mg/kg, to NARs, the plasma protein binding of torasemide was 23.3% in the rats due to binding to α ‐ and β ‐globulins (this value, 23.3%, was greater than only 12% for furosemide), and hence the percentages of intravenous dose of torasemide excreted in 8‐h urine as unchanged drug was 14.9% in the rat (this value was considerably greater than only 7% for furosemide). After intravenous administration of torasemide to NARs, the AUC (301 versus 2680 µg/min/ml) was significantly smaller [due to significantly faster both Cl r (4.81 versus 0.386 ml/min/kg) and Cl nr (28.3 versus 3.33 ml/min/kg)], terminal half‐life (18.3 versus 73.5 min) and mean residence time (6.97 versus 61.8 min) were significantly shorter (due to faster Cl, 33.2 versus 3.74 ml/min/kg), and amount of 8‐h urinary excretion of unchanged torasemide (446 versus 323 µg, due to increase in intrinsic renal excretion) was significantly greater than those in control rats. The 8‐h urine output and 8‐h urinary excretions of sodium and chloride were comparable between two groups of rats although the 8‐h urinary excretion of torasemide was significantly greater in NARs. This could be explained by the following. The amount of urinary excretion of torasemide was significantly greater in NARs than that in control rats only between 0 and 30 min urine collection. In both groups of rats, the urinary excretion rate of torasemide during 0–30 min reached an upper plateau with respect to urine flow rate as well urinary excretion rates of sodium and chloride. Therefore, the diuretic effects (8‐h urine output and 8‐h urinary excretions of sodium and chloride) were not significantly different between the two groups of rats. Copyright © 2002 John Wiley & Sons, Ltd.