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Research ArticleArticle

Pharmacokinetics and Pharmacodynamics of Intravenous Azosemide in Mutant Nagase Analbuminemic Rats

Eun J. Kim, Ae K. Lee, So H. Kim, Sang G. Kim and Myung G. Lee
Drug Metabolism and Disposition February 2003, 31 (2) 194-201; DOI: https://doi.org/10.1124/dmd.31.2.194
Eun J. Kim
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Ae K. Lee
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So H. Kim
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Sang G. Kim
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Myung G. Lee
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Abstract

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.

Footnotes

  • This work was supported in part by a grant from the Republic of Korea Ministry of Health and Welfare (01-PJ1-PG3-21700-0003), 2001-2003.

  • Abbreviations used are::
    Azosemide
    5-(4-chloro-5-sulfamoyl-2-thenylaminophenyl)-tetrazole
    NARs
    Nagase analbuminemic rats
    M1
    5-(2-amino-4-chloro-5-sulfamoylphenyl)-tetrazole
    HPLC
    high-performance liquid chromatographic
    AST
    aspartate transaminase
    ALT
    alanine transaminase
    ADH
    antidiuretic hormone
    P450
    cytochrome P450
    SSPE
    standard saline/phosphate/EDTA
    CLint
    intrinsic M1 formation clearance
    AUC
    area under the plasma concentration–time curve from time zero to time infinity
    CL
    time-averaged total body clearance
    MRT
    mean residence time
    Vss
    apparent volume of distribution at steady state
    CLR
    time-averaged renal clearance
    CLNR
    time-averaged nonrenal clearance
    CLCR
    creatinine clearance
    Emax
    maximal diuretic effect
    Ae
    total amount excreted in urine as unchanged drug
    GIM1, 0–8 h
    greater percentage of M1 recovered from gastrointestinal tract at 8 h
    • Received June 4, 2002.
    • Accepted November 7, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (2)
Drug Metabolism and Disposition
Vol. 31, Issue 2
1 Feb 2003
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Research ArticleArticle

Pharmacokinetics and Pharmacodynamics of Intravenous Azosemide in Mutant Nagase Analbuminemic Rats

Eun J. Kim, Ae K. Lee, So H. Kim, Sang G. Kim and Myung G. Lee
Drug Metabolism and Disposition February 1, 2003, 31 (2) 194-201; DOI: https://doi.org/10.1124/dmd.31.2.194

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Research ArticleArticle

Pharmacokinetics and Pharmacodynamics of Intravenous Azosemide in Mutant Nagase Analbuminemic Rats

Eun J. Kim, Ae K. Lee, So H. Kim, Sang G. Kim and Myung G. Lee
Drug Metabolism and Disposition February 1, 2003, 31 (2) 194-201; DOI: https://doi.org/10.1124/dmd.31.2.194
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