Effect of Azosemide on the in vitro Perfused Thick Ascending Limb of Henle&amp;rsquo;s Loop from the Mouse

Tsuchiya, Ken; Sasaki, Sei; Marumo, Fumiaki

doi:10.1159/000138718

Cited by 2 publications

(1 citation statement)

References 11 publications

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“…Its main site of action has been reported to be the thick ascending limb of the loop of Henle in humans using a standard clearance technique [1], in rats using a free-flow micropuncture method [32], and in mice using an in vitro perfused method [33]. The diuretic, 40 mg, was administered orally once to eight healthy male volunteers during water loading and during hydropenia [1].…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of azosemide

Suh¹,

Kim²,

Lee³

2003

Biopharm & Drug Disp

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Azosemide is used in the treatment of oedematous states and hypertension. The exact mechanism of action is not fully understood, but it mainly acts on both the medullary and cortical segments of the thick ascending limb of the loop of Henle. Delayed tolerance was demonstrated in humans by homeostatic mechanisms (principally an increase in aldosterone secretion and perhaps also an increase in the reabsorption of solute in the proximal tubule). After oral administration to healthy humans in the fasting state, the plasma concentration of azosemide reached its peak at 3-4 h with an absorption lag time of approximately 1 h and a terminal half-life of 2-3 h. The estimated extent of absolute oral bioavailability in humans was approximately 20.4%. After oral administration of the same dose of azosemide and furosemide, the diuretic effect was similar between the two drugs, but after intravenous administration, the effect of azosemide was 5.5-8 times greater than that in furosemide. This could be due to the considerable first-pass effect of azosemide. The protein binding to 4% human serum albumin was greater than 95% at azosemide concentrations ranging from 10 to 100 microg/ml using an equilibrium dialysis technique. The poor affinity of human tissues to azosemide was supported by the relatively small value of the apparent post-pseudodistribution volume of distribution (Vdbeta), 0.262 l/kg. Eleven metabolites (including degraded products) of azosemide including M1, glucuronide conjugates of both M1 and azosemide, thiophenemethanol, thiophencarboxylic acid and its glycine conjugate were obtained in rats. Only azosemide and its glucuronide were detected in humans. In humans, total body clearance, renal clearance and terminal half-life of azosemide were 112 ml/min, 41.6 ml/min and 2.03 h, respectively. Azosemide is actively secreted in the renal proximal tubule possibly via nonspecific organic acid secretory pathway in humans. Thus, the amount of azosemide that reaches its site of action could be significantly modified by changes in the capacity of this transport system. This capacity, in turn, could be predictably changed in disease states, resulting in decreased delivery of the diuretic to the transport site, as well as in the presence of other organic acids such as nonsteroidal anti-inflammatory drugs which could compete for active transport of azosemide. The urinary excretion rate of azosemide could be correlated well to its diuretic effects since the receptors are located in the loop of Henle. The diuretic effects of azosemide were dependent on the rate and composition of fluid replacement in rabbits; therefore, this factor should be considered in the evaluation of bioequivalence assessment.

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Section: Mechanism Of Actionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of azosemide

Suh¹,

Kim²,

Lee³

2003

Biopharm & Drug Disp

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Pharmacokinetic changes in drugs during protein-calorie malnutrition: correlation between drug metabolism and hepatic microsomal cytochrome p450 isozymes

2004

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The rats with protein-calorie malnutrition (PCM, 5% casein diet for a period of 4-week) were reported to exhibit 60 and 80% suppression in the hepatic microsomal cytochrome P450 (CYP) 1A2 and CYP2C11 levels, respectively, and 40-50% decreases in CYP2E1 and CYP3A1/2 levels compared to control (23% casein diet for a period of 4-week) based on Western blot analysis. In addition, Northern blot analysis showed that CYP1A2, CYP2E1, CYP2C11, and CYP3A1/2 mRNAs decreased in the state of PCM as well. Hence, pharmacokinetic changes of the drugs in rats with PCM [especially the area under the plasma concentration-time curve from time zero to time infinity (AUC) changes of metabolite(s)] reported from literatures were tried to explain in terms of CYP isozyme changes in the rats. Otherwise, the time-averaged nonrenal clearance (CL NR) of parent drug was compared. Pharmacokinetic changes of the drugs in other types of malnutritional state, such as kwashiorkor and marasmus, in both human and animal models were also compared. The drugs reviewed are as follows: diuretics, antibiotics, anticancer agents, antiepileptics, antiarrythmics, analgesics, xanthines, antimalarials, and miscellaneous.

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Effect of Azosemide on the in vitro Perfused Thick Ascending Limb of Henle’s Loop from the Mouse

Cited by 2 publications

References 11 publications

Pharmacokinetics and pharmacodynamics of azosemide

Pharmacokinetics and pharmacodynamics of azosemide

Pharmacokinetic changes in drugs during protein-calorie malnutrition: correlation between drug metabolism and hepatic microsomal cytochrome p450 isozymes

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