RT Journal Article
SR Electronic
T1 Pharmacokinetics and Pharmacodynamics of Intravenous Azosemide in Mutant Nagase Analbuminemic Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 194
OP 201
DO 10.1124/dmd.31.2.194
VO 31
IS 2
A1 Eun J. Kim
A1 Ae K. Lee
A1 So H. Kim
A1 Sang G. Kim
A1 Myung G. Lee
YR 2003
UL http://dmd.aspetjournals.org/content/31/2/194.abstract
AB This paper reports 1) the increase in expression of CYP1A2 in mutant Nagase analbuminemic rats (NARs), 2) the role of globulin binding of azosemide in circulating blood in its urinary excretion and hence its diuretic effects in NARs, and 3) the significantly faster renal (CLR) and nonrenal (CLNR) clearances of azosemide in NARs. Azosemide (mainly metabolized via CYP1A2 in rats), 10 mg/kg, was intravenously administered to control rats and NARs. Northern and Western blot analyses revealed that the expression of CYP1A2 increased ∼3.5-fold in NARs as compared with control. The plasma protein binding of azosemide in control rats and NARs was 97.9 and 84.6%, respectively. In NARs, plasma protein binding (84.6%) was due to binding to α- (82.6%) and β- (68.9%) globulins. In NARs, the amount of unchanged azosemide excreted in 8-h urine was significantly greater (37.7 versus 21.0% of intravenous dose) than that in control rats due to an increase in intrinsic renal active secretion of azosemide. Accordingly, the 8-h urine output was significantly greater in NARs. The area under the plasma concentration–time curve of azosemide was significantly smaller (505 versus 2790 μg · min/ml) in NARs because of markedly faster CLR (7.36 versus 0.772 ml/min/kg, secondary to a significant increase in urinary excretion of azosemide and intrinsic renal active secretion). Additionally, CLNR was significantly faster (12.4 versus 3.05 ml/min/kg, because of ∼3.5 fold increase in CYP1A2) in NARs compared with control. Based on in vitro hepatic microsomal studies, the intrinsic M1 [a metabolite of azosemide; 5-(2-amino-4-chloro-5-sulfamoylphenyl)-tetrazole] formation clearance was significantly faster (67.0% increase) in NARs than that in control rats, and this supports significantly faster CLNR in NARs. Renal sensitivity to azosemide was significantly greater in NARs than in control rats with respect to 8-h urine output (385 versus 221 ml/kg) and 8-h urinary excretions of sodium, potassium, and chloride. This study supports that in NARs, binding of azosemide to α- and β-globulins in circulating blood play an important role in its diuretic effects. The American Society for Pharmacology and Experimental Therapeutics