Pharmacokinetics and pharmacodynamics of azosemide after intravenous and oral administration to rats: Absorption from various GI segments

Lee, Sun H.; Lee, Myung G.

doi:10.1007/bf02353480

Cited by 21 publications

(51 citation statements)

References 23 publications

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“…This indicates that azosemide is actively secreted in both groups of rats. Active renal secretion of azosemide was also found in other rat studies (Lee and Lee, 1996). Considering the CL R of azosemide (Table 3) and reported kidney blood flow in rats (36.8 ml/min/kg) (Davies and Morris, 1993) and hematocrit (Table 1), the estimated renal extraction ratios (CL R / renal plasma flow) of azosemide were 3.63 and 36.7% for control rats and NARs, respectively.…”

Section: Discussionsupporting

confidence: 73%

“…The V ss was significantly larger in NARs (Table 3), which could be due to higher concentrations of tissue globulins in NARs (Renkin et al, 1993) and 6.3-fold increase in free fraction of azosemide in plasma (Table 1). The larger V ss of azosemide due to increased free fraction in plasma has also been reported in Sprague-Dawley rats (Lee and Lee, 1996). The V ss of furosemide was also significantly greater in NARs than that in control rats (Inoue et al, 1987).…”

Section: Fig 3 Arterial Plasma Concentration-time Profiles Of Azosesupporting

confidence: 58%

“…Smith and Benet (1982) found that the ability to excrete furosemide in the urine was independent of plasma protein binding because furosemide is highly bound (i.e., Ͼ 96% to plasma protein), and it appears that the majority of furosemide available for excretion in the urine is delivered by active secretion rather than passive filtration (Ponto and Schoenwald, 1990). This could also be applied to bumetanide (Odlind et al, 1983) and azosemide (Lee and Lee, 1996). In NARs, the contribution of passive filtration to total excretion of unchanged azosemide was 9.16%.…”

Section: Fig 3 Arterial Plasma Concentration-time Profiles Of Azosementioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Intravenous Azosemide in Mutant Nagase Analbuminemic Rats

Kim

Lee²,

Kim³

et al. 2003

Drug Metab Dispos

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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 (CL R ) and nonrenal (CL NR ) 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 ϳ3.5-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 ␣-(82.6%) and ␤-(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 g ⅐ min/ml) in NARs because of markedly faster CL R (7.36 versus 0.772 ml/min/kg, secondary to a significant increase in urinary excretion of azosemide and intrinsic renal active secretion). Additionally, CL NR was significantly faster (12.4 versus 3.05 ml/min/kg, because of ϳ3.5 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 CL NR 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 ␣-and ␤-globulins in circulating blood play an important role in its diuretic effects.Azosemide 1 [5-(4-chloro-5-sulfamoyl-2-thenylaminophenyl)-tetrazole] is a sulfonamide loop diuretic closely resembling furosemide in its diuretic action (Krück et al., 1978). Its main sites of action are both the cortical and medullary segments of the thick ascending limb of loop of Henle (Brater, 1979) where it inhibits water and solute reabsorption. It is used clinically in the treatment of edematous states and arterial hypertension; specific indications are cardiac and renal edema and ascites (Michel, 1992). Eleven metabolites of azosemide were found in rat urine and bile (Asano et al., 1984), but the diuretic effect of the drug does not require metabolism to an active metabolite (Greven, 1991).After i.v. administration of furosemide to mutant Nagase analbuminemic rats (NARs), an animal model for human familial analbuminemia, the diuretic effects of the drug (urine output and urinary e...

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Section: Discussionsupporting

confidence: 73%

Section: Fig 3 Arterial Plasma Concentration-time Profiles Of Azosesupporting

confidence: 58%

Section: Fig 3 Arterial Plasma Concentration-time Profiles Of Azosementioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Intravenous Azosemide in Mutant Nagase Analbuminemic Rats

Kim

Lee²,

Kim³

et al. 2003

Drug Metab Dispos

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“…The procedures used to determine biliary excretion were similar to those reported previously (25). In the early morning, the jugular vein and the bile duct of each rat were cannulated with polyethylene tubing (Clay Adams, Parsippany, N.J.) while each rat was lightly anesthetized with ether.…”

Section: Methodsmentioning

confidence: 99%

Dose-Dependent Pharmacokinetics of Itraconazole after Intravenous or Oral Administration to Rats: Intestinal First-Pass Effect

Shin

Choi

Kim

et al. 2004

Antimicrob Agents Chemother

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The dose-dependent pharmacokinetics of itraconazole after intravenous (10, 20, or 30 mg/kg) and oral (10, 30, or 50 mg/kg) administration and the first-pass effects of itraconazole after intravenous, intraportal, intragastric, and intraduodenal administration at a dose of 10 mg/kg were evaluated in rats. After intravenous administration at a dose of 30 mg/kg, the area under the plasma concentration-time curve from time zero to infinity (AUC 0-ؕ ) was significantly greater than those at 10 and 20 mg/kg (1,090, 1,270, and 1,760 g ⅐ min/ml for 10, 20, and 30 mg/kg, dose-normalized at 10 mg/kg). After oral administration, the AUC 0-ؕ was significantly different for three oral doses (380, 687, and 934 g ⅐ min/ml for 10, 30, and 50 mg/kg, respectively, dosenormalized at 10 mg/kg). The extent of absolute oral bioavailability (F) was 34.9% after an oral dose at 10 mg/kg. The AUC 0-ؕ (or AUC 0-8 h ) values were comparable between intravenous and intraportal administration and between intragastric and intraduodenal administration, suggesting that the hepatic and gastric first-pass effects were almost negligible in rats. However, the AUC 0-8 h values after intraduodenal and intragastric administration were significantly smaller than that after intraportal administration, approximately 30%, suggesting that the intestinal first-pass effect was approximately 70% of that of an oral dose of 10 mg/kg. The low F after oral administration of itraconazole at a dose of 10 mg/kg could be mainly due to the considerable intestinal first-pass effect.The pharmacokinetics of itraconazole after oral administration to humans (10-12), rats (11,22,31), and rabbits, cats, and dogs (11) have been reported; however, data on the pharmacokinetics after intravenous administration to humans (12), dogs (11), and rats (22, 31) are scarce. It has been reported (12) that after oral administration of itraconazole to humans, the values for the area under the plasma concentration-time curve from time zero to infinity (AUC 0-ϱ ) for the drug were dose dependent (increased in proportion to dose increases); 50, 100, and 200 mg by capsule after a meal and 100 and 200 mg by capsule after breakfast. However, the dose-dependent pharmacokinetics of itraconazole after intravenous administration and the first-pass effects of the drug have not been reported. It has been reported (31) that the hepatic first-pass effect of itraconazole was estimated to be 18.5% in rats.The purpose of this paper is to report the dose-dependent pharmacokinetics of itraconazole after intravenous (at doses of 10, 20, and 30 mg/kg) and oral (at doses of 10, 30, and 50 mg/kg) administration to rats and the intestinal first-pass effect of itraconazole after intravenous, intraportal, intragastric, and intraduodenal administration (at a dose of 10 mg/kg) to rats. MATERIALS AND METHODSChemicals. Sporanox intravenous solution (10 mg/ml as itraconazole as a solution in hydroxylpropyl-␤-cyclodextrin [HP-␤-CD], sorbitol, propylene glycol, HCl, NaOH, and water for injection; lot no. 01-D01A-IW), Spor...

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“…Standard methods [10] were used to calculate the following pharmacokinetic parameters after intravenous administration; the area under the plasma concentration-time curve from time zero to time infinity (AUC) [11], time-averaged total body clearance (Cl), area under the first moment of plasma concentration-time curve (AUMC), mean residence time (MRT), apparent volume of distribution at steady-state (V ss ), and the time-averaged renal (Cl r ) and nonrenal (Cl nr ) clearances [12,13].…”

Section: Pharmacokinetic Analysismentioning

confidence: 99%

Gender differences in pharmacokinetics and pharmacodynamics of azosemide in rats

Lee

Han

Lee

1999

Biopharm. Drug Dispos.

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Pharmacokinetics and pharmacodynamics of azosemide after intravenous and oral administration to rats: Absorption from various GI segments

Cited by 21 publications

References 23 publications

Pharmacokinetics and Pharmacodynamics of Intravenous Azosemide in Mutant Nagase Analbuminemic Rats

Pharmacokinetics and Pharmacodynamics of Intravenous Azosemide in Mutant Nagase Analbuminemic Rats

Dose-Dependent Pharmacokinetics of Itraconazole after Intravenous or Oral Administration to Rats: Intestinal First-Pass Effect

Gender differences in pharmacokinetics and pharmacodynamics of azosemide in rats

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